Immunol Res (2015) 61:169–171 DOI 10.1007/s12026-014-8592-2


Hepatopulmonary syndrome associated with visceral leishmaniasis Nihal Martis • Christelle Pomares • Pierre Yves Jeandel Thierry Lazure • Pierre Marty • Eric Rosenthal

Eric Rosenthal

Published online: 13 November 2014 Ó Springer Science+Business Media New York 2014

Abstract Leishmaniasis caused by Leishmania infantum is endemic in the Mediterranean region. Its visceral form can present a diagnostic challenge owing to the disease’s wide spectrum of clinical presentations. We describe the very atypical case of a 66-year-old male Caucasian patient with hepatopulmonary syndrome and an exceptionally rare expression of visceral leishmaniasis in a disseminated form with mucocutaneous involvement presenting as an autoimmune systemic disease. Keywords Leishmaniasis infantum  Visceral leishmaniasis  Mucocutaneous  Hepatopulmonary syndrome  Autoimmune  Cryoglobulinemia  Amphotericin B


Case report

Leishmaniasis caused by the protozoon Leishmania infantum is not uncommon in the Mediterranean region, and notably in the South of France [1]. It can, however, present as a diagnostic challenge owing to the disease’s wide spectrum of clinical presentations [2]. Our case illustrates how autochthonous forms may present as an autoimmune systemic disease and can be misdiagnosed outside endemic regions. To our knowledge, this is the first report of hepatopulmonary syndrome associated with chronic visceral leishmaniasis (VL).

A 66-year-old male Caucasian patient presented with chronic crust-forming rhinitis, hoarseness and chronic respiratory failure requiring supplemental oxygen. He had recently been diagnosed in Paris with hepatopulmonary syndrome (HPS) of unknown origin and was being prepared for a liver transplant. He was known to have a history of chronic bi-cytopenia and splenomegaly 10 years prior to his current symptoms. Splenectomy that had been performed at the time was neither diagnostic nor therapeutic. The patient resided throughout the year in Nice (Southern France). On admission, the patient showed no signs of distress. Clinical examination was unremarkable apart from nail clubbing and hepatomegaly. There were no signs of heart failure, platypnea nor orthodeoxia. Examination of the skin was normal. Spirometry had shown partially reversible obstructive lung disease. Transfer factor of the lung for carbon monoxide was 41 % of the predicted value. Blood count showed microcytic anemia with a hemoglobin level of 11.9 g/dL, neutropenia at 0.1 G/L, and normal lymphocyte and platelet counts. Bone marrow aspiration revealed a 2.5 % plasma cell count and moderate lymphocytosis at 16 %. Bone marrow biopsy material was

N. Martis  P. Y. Jeandel  E. Rosenthal (&) Service de Me´decine Interne, Centre Hospitalier Universitaire de Nice, 151 route de Saint-Antoine de Ginestie`re, 06200 Nice, France e-mail: [email protected] C. Pomares  P. Marty Service de Parasitologie-Mycologie, Centre Hospitalier Universitaire de Nice – Universite´ de Nice-Sophia-Antipolis, C3 M INSERM 1065, Nice, France T. Lazure Service d’Anatomo-Pathologie, AP-HP Hoˆpital Biceˆtre, Le Kremlin-Biceˆtre, France



Diagnostics and Environmental Factors (2015) 61:169–171

retrospectively found evidence of L. infantum and PCR on the biopsy samples was positive. Anamnesis revealed that the patient had owned a dog suffering from leishmaniasis.


Fig. 1 Beneath the oral mucosa, heavy infiltrate of lymphocytes, plasma cells, histiocytes and giant cells with intracytoplasmic Leishman–Donovan bodies (Hematein Eosin Saffron 91,200)

poor and was not diagnostic. Glomerular filtration rate was estimated at 34.4 mL/mn. Liver enzyme testing showed elevated gamma-glutamyltransferase and alkaline phosphatase levels at twice the normal range with normal transaminase levels. C-reactive protein was normal. Urinalysis was normal and proteinuria was absent. Serological testing for HIV, viral hepatitis, CMV, EBV, Parvovirus B19 and Toxoplasma was negative. Immunological investigations found evidence of type II cryoglobulinemia with decreased CH50 complement and positive rheumatoid factor. Anti-nuclear factors were borderline positive (titer 1/80)—anti-dsDNA, anti-histone and anti-smooth muscle antibodies were positive. ANCA and anti-citrullinated peptide antibodies were negative. Monoclonal IgG-lambda paraproteinemia was identified with a serum protein electrophoresis peak at 12.5 g/L. The j/k ratio was normal (Fig. 1). Full body computerised tomography scanning was uninformative and did not show evidence of arteriovenous malformations. Contrast echocardiography, however, did show evidence of right-to-left shunt that was confirmed by scintigraphy. Hepatopulmonary syndrome was considered based on elevated portal pressure (hepatic venous pressure gradient at 9 mmHg) and severe hypoxemia with an arterial–alveolar difference of 60 mmHg. Perisinusoidal fibrosis with lymphoplasmocytic infiltrates was present on the liver biopsy. Bronchoscopy was carried out to investigate the crust-forming rhinitis and hoarseness. Biopsies of the respiratory tract and the ENT-sphere showed granulomatous lesions. Further analysis of these granulomatous lesions on the vocal cords revealed amastigote forms of Leishmania sp. Serological testing for Leishmania sp. was positive (IFAT and Western Blot) as was Leishmania sp. polymerase chain reaction (PCR) on peripheral blood samples. Histopathology of the operative specimen from the splenectomy performed nearly a decade ago


Leishmaniasis caused by L. infantum is a parasitic disease transmitted through the bites of Phlebotomus sandflies. Leishmania amastigote forms target mononuclear phagocytes. Clinical expression of Leishmania infection ranges from asymptomatic carriage to fatal visceral disease if the infection is left untreated. In the Mediterranean region, L. infantum is mostly responsible for visceral forms; cutaneous lesions are seldom found. Mucosal leishmaniasis, on the other hand, is a rare form of the disease and is potentially life threatening due to visceralization [2]. Generally, VL manifests itself through persistent fever (resistant to antibiotics), weight loss, hepato-splenomegaly and marked pancytopenia. In HIV-infected patients, VL is an opportunistic disease [3]. Since the advent of combination antiretroviral therapy, long-term persistence of circulating Leishmania species may be observed, leading to active chronic VL, a condition alternating symptomatic and asymptomatic phases [4]. In a subset of patients with a prolonged course of active chronic VL, renal injury potentially mediated by immune complex deposition has been recently described [5]. This case report suggests that hepatopulmonary syndrome may be associated with prolonged Leishmania infection. Misdiagnosis of autochthonous visceral VL is relatively common outside endemic regions. The condition can be initially misdiagnosed as an autoimmune disease because LV may mimic diseases such as systemic lupus erythematosus, autoimmune hepatitis and dermatomyositis. Polyclonal hypergammaglobulinemia is a well-established finding and is attributed to chronic antigenic stimulation. Autoantibodies to ribonucleoproteins found in sera of infected patients are not only a consequence of polyclonal lymphocytic activation, but may also result from molecular mimicry between leishmanial antigens and ribonucleoproteins. Various biological signs of auto-immunity seem to be induced by leishmaniasis infection. Anti-Sm, RNP, SS-A and SS-B antibodies have been reported in high titers in numerous patients with visceral leishmaniasis [6]. Autoantibodies of patients with chronic parasitic infections may have a direct immuno-pathogenic role in determining the clinical manifestations of the parasitic diseases, and other immune-mediated damage may be involved [7]. Our patient presented with type II cryoglobulinemia. Though relatively infrequent in leishmaniasis, mixed cryoglobulinemic vasculitis secondary to VL and type III membranoproliferative glomerulonephritis, attributed to Leishmania

Diagnostics and Environmental Factors (2015) 61:169–171

antigens-containing immune complex deposition in the kidney, have been reported [5, 8]. VL has rarely been defined as a cause of liver fibrosis and portal hypertension [9]. Portal hypertension usually results from changes in splanchnic vasculature as seen in liver biopsy material, and fibrosis is probably only present in later stages of the disease. Pro-inflammatory mediators (i.e., IL-10, IFNc, TNF) are known to enhance inducible nitric oxide synthase in infected tissue and impact vasculature through increased vasodilatation [2]. HPS is characterized by a defect in arterial oxygenation induced by vascular dilatation associated with hepatic disease [10]. Although HPS is more commonly associated with cirrhotic portal hypertension, there is no correlation between HPS and the primary cause of liver disease or the extent of liver dysfunction [10]. To our knowledge, HPS due to Leishmania infection has not been previously reported. On the other hand, HPS is a well-known complication described in patients with Schistosoma mansoni periportal fibrosis and portal hypertension [11]. In this case report, the role of prolonged infection with Leishmania on perisinusoidal fibrosis and on HPS deserves further investigations. In our patient, intravenous liposomal amphotericin B (LAmB) was preferred to antimonial compounds and a 6-day treatment-strategy was adopted. L-AmB was administered for 5 days at a dose of 4 mg/kg/day and repeated once on day 10. Treatment tolerance was excellent throughout. Within 6 months of treatment, parasitic load estimated by PCR became undetectable on peripheral blood. Clinical presentation improved as ENT signs disappeared and oxygen requirement decreased, although lung function currently remains impaired. Biological anomalies regressed with antiparasitic treatment, as did paraproteinemia. Diagnosis of VL in its disseminated form with mucocutaneous involvement had taken 10 years, during which complications of the disease had waylaid clinicians. Connective tissue disease, vasculitides and malignant hematological disorders had been suspected. This clinical case illustrates the challenges presented by autochthonous VL. Prolonged infection with Leishmania sp. and complex host–parasite relationships may lead to rare and yet undescribed manifestations. Hepatopulmonary syndrome could be added to the list of such manifestations. Retrospectively, had the patient’s habitus been taken into account, this form


of VL could have been suspected and might have avoided a decade of diagnostic uncertainty. Conflict of interest


References 1. Ready PD. Epidemiology of visceral leishmaniasis. Clin Epidemiol. 2014;6:147–54. doi:10.2147/CLEP.S44267. 2. Bogdan C. Leishmaniasis in rheumatology, haematology and oncology: epidemiological, immunological and clinical aspects and caveats. Ann Rheum Dis. 2012;71(Suppl 2):i60–6. doi:10. 1136/annrheumdis-2011-200596. 3. Rosenthal E, Marty P, Poizot M, Reynes J, Platlong F, Lafeuillade A, Jaubert D, Boulat O, Dereure G, Gamabarelli A. Visceral leishmaniasis and HIV-1 co-infection in Southern France. Trans R Soc Trop Med Hyg. 1995;89:159–62. 4. Bourgeois N, Bastien P, Reynes J, Makinson A, Rounet I, Lachaud L. Active chronic visceral leishmaniasis’’ in HIV-infected patients demonstrated by biological and clinical long-term follow-up of 10 patients. HIV Med. 2010;11(Suppl 10):670–3. doi:10.1111/j.1468-1293.2010.00846.x. 5. Vassallo M, Moranne O, Ambrosetti D, Jeandel PY, Pomares C, Cassuto E, Boscagli A, Giraud G, Montagne N, Dentone C, Demacina I, Villaggio B, Secondo G, Ferrea G, Passeron C, Saudes L, Kaphan R, Marty P, Rosenthal E. Visceral leishmaniasis due to Leishmania infantum with renal involvement in HIVinfected patients. BMC Infect Dis. 2014;14(1):561 (Epub ahead of print). 6. Argov S, Jaffe CL, Krupp M, Slor H, Shoenfeld Y. Autoantibody production by patients infected with Leishmania. Clin Exp Immunol. 1989;76:190–7. 7. Abu-Shakra M, Buskila D, Shoenfeld Y. Molecular mimicry between host and pathogen: examples from parasites and implication. Immunol Lett. 1999;67:147–52. 8. Rizos E, Dimos G, Liberopoulos EN, Elisaf MS, Drosos AA. Cryoglobulinemic purpura in visceral leishmaniasis. Rheumatol Int. 2005;25(6):469–71. doi:10.1007/s00296-004-0533-2. 9. Prasad R, Singh UK, Mishra OP, Jaiswal BP, Muthusami S. Portal hypertension with visceral leishmaniasis. Indian Pediatr. 2010;47(11):965–7. 10. Rodriguez-Roisin R, Krowka MJ. Hepatopulmonary syndrome. A liver-induced lung vascular disorder. N Engl J Med. 2008;358:2378–87. doi:10.1056/NEJMra0707185. 11. Ferreira R de C, Domingues AL, Markman Filho B, Veras FH, Batista LJ, Albuquerque Filho ES. Hepatopulmonary syndrome in patients with Schistosoma mansoni periportal fibrosis. Acta Trop. 2009;111(2):119–24. doi:10.1016/j.actatropica.2009.03. 005. Epub 2009 Mar 25.


Hepatopulmonary syndrome associated with visceral leishmaniasis.

Leishmaniasis caused by Leishmania infantum is endemic in the Mediterranean region. Its visceral form can present a diagnostic challenge owing to the ...
307KB Sizes 4 Downloads 21 Views