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ABDOMINAL SURGERY

Official Journal of the American Society of Abdominal Surgeons, Inc.

This article originally appeared in the Winter 2013 / Spring 2014 issue of the Journal.

Splenectomy as a method of diagnosisof Visceral Leishmaniasis in HIV patient. Case report and review the literature.

Mella Laborde M,1 Jover-Díaz F,2
Nofuentes Riera C,1 Garcia Marín A,1
Perez Bru S,3 Soliveres Soliveres E,3
Vander Hofstadt JM,†1 Mayol Belda MJ,4
Garcia García S,5 Compañ Rosique1


1Assistant Surgeon, Department of Surgery,
Hospital Universitario San Juan de Alicante, Spain
2Unit Infectous Disease, Hospital Universitario San
Juan de Alicante, Alicante, Spain
3Surgical Resident Department of Surgery, Hospital
Universitario, San Juan de Alicante, Spain
4Head of Department of Pathology, Hospital
Universitario, San Juan de Alicante, Alicante, Spain
5Head of Department of Surgery, HospitalUniversitario, San Juan de Alicante. Alicante, Spain

Address for correspondence:
Mario Mella Laborde
Carretera Valencia s/n. Alicante, Spain 03550
Tel: 0034-965938611
Email: wmarietem@hotmail.com


ABSTRACT

Background
Leishmaniasis is a globally prevalent parasitic disease. Subclinical visceral leishmaniasis can be found at anystage of HIV-1 infection, but symptomatic cases of infection appear mainly when a deep immunosuppressionis present.

Material and Methods
Report of a case in a HIV patient with visceral leishmaniasis diagnosed by splenectomy.

Results
We present a case of 38-year-old male with infection HIVstage C-3, who presents hepatosplenomegaly of 20 cm, pancytopenia and undetectable viral load HIV in bloodserum. The numbers of lymphocytes CD4 were of 186/ml. The biopsy of bone marrow showed absence of atipias cellular and a plasmocitosis of 6% with absence of parasites intracellulares. Before the possibility of aprimary splenic lymphoma, carried out an openedsplenectomy. The analysis of the piece showed the existence of abundant parasites compatible with Leishmania.

Conclusions
Splenectomy as a method of diagnosis of Visceral Leishmaniasis in HIV patient must be reserved as last resource.

SHORT SUMMARY
Leishmaniasis is a prevalent parasitic disease which is rare in Western Europe and occur more frecuently in patients when immunosuppression conditions are present.

INTRODUCTION
The visceral Leishmaniasis (VL) or Kala-Azar is a zoonosis produced by flagellated parasites which reservoir areanimal vertebrates (dogs, rates) and the man. Leishmaniais a parasite intracellular obliged, that affects with majorfrequency children and whose arthropod vector is afemale mosquito belonging to the family Phlebotomidae.It is estimated that 12 million persons in the world areinfected by Leishmania and near 350 millions in 88 countriespresent risk of infection, concerning with majorfrequency to developing countries.1 Approximately there are 2 million new cases in the world, most appears shaped like cutaneous Leishmaniasis (1,5 millions)2 and the rest(0,5 millions) shaped like visceral Leishmaniasis.3 The latteris mainly found in South of Asia, East Africa and Brazil.

It has described 20 species of Leishmania that are pathogenicfor human.4 The causal agent of the VL are diverse:L. Donovani, is distributed fundamentally in India, Asia,and Africa; L. Infantum or L.Chagasi, with predominancein south-east of Europe and north of Africa; L.Tropica, L.braziliensis, L. Mexican, and L. amazonensis are frequentin South America. In Spain the number of cases of coinfectionHIV /VL published by the WHO from January 1990 until December 2006 is 2476 cases.5,6

Habitually the diagnosis is realized by mean of notinvasive methods (serology) or invasive (puncture of bonemarrow or biopsy of lymphadenopathy). However, there are few studies of the diagnosis after splenectomy.7

CASE REPORT
We present a case of 38-year-old male with infection HIV stage C-3, previously operated of a seminoma testicular without adjuvant treatment.In clinical follow-up he presents hepatosplenomegaly of 20 cm in abdominal CTScan (Figure 1). The blood test emphasized a pancytopenia and the inventory of viral load HIV in blood serumwas undetectable. The numbers of lymphocytes CD4 wereof 186/ml. The biopsy of bone marrow showed absenceof cellular atipias in three hematologic series and a plasmocitosisof 6% with absence of intracellular parasites.Patient was not presenting other concomitant opportunists diseases. Because of the possibility of a primarysplenic lymphoma, an opened splenectomy wasper formed. Analysis of the piece (Figure 2,3) showedthe existence of abundant parasites compatible with Leishmania. He received later treatment with Liposomal amphotericin B in secondary prevention.

DISCUSSION
The first case of VL associated with HIV was described in 1985.8 Its natural history has been modified, so that the risk of suffering it in patients endemic areas that presentinfection for HIV has increased between 100-2, 320 times diminishing the probability of response to the treatment.9,10,11 Actually the global incident of co-infection is underestimated. In turn VL determines a clinical progressionin patients with HIV and the development of AIDS. In endemic areas it thinks that those people who presentone VL have a risk of co-infection HIV-Leishmanias is between 2-9%12 though it seems that this proportion is increasing in countries as Ethiopia where numbers reach between 15-30%.13 In the countries of South Europe as France, Spain, Portugal and Italy a significant reduction hasbeen demonstrated in the number of people affected from 1990 by 1440 cases up to the 299 in the following decade due to the use of the anti-retroviral therapy.7 In developing countries, this has not happened because of the limited access that it is had to the anti-retroviral medication, having for example India an annual incident estimated of 250.000 cases.14 There have been described 3 principal factors of risk which are: the use of drugs for parenteral route with syringes infected by Leishmania15,16,17 (more important factor, more frequent factor in the age before the use of theanti-retroviral therapy), the sexual activity in heterosexuals, that it showed an increase of incident between 2001-2006 in west Europe and in homosexuals where it has not been observed an increase of incident between the age pre and post therapy anti-retroviral drug.18

Performance targets of HIV and Leishmania are the cellular immunity. Those persons who are inmunosuppressed with count of Lymphocytes CD4 + <200 will have major probability of developing VL. Our patient presented 186 lymphocytes CD4+/ml. The immune response opposite to the infection for Leishmania is happened by lymphocytes Th1 and Th2, which produce a series of cytokines: IL-2,IL-3, IL-12, INF-γ, which in turn activate macrophages inorder to eliminate promastigotes by phagocytosis.

CLINIC
The average age of presentation is 38 years with high frequency in male, as our patient. The period of incubation changes between 3-8 months (10 days to 34 months)5The most frequent form of clinical presentation consists of a subacute episode (weeks or months) with fever, weakness, night perspiration, anorexia and loss of weight.19 Hepatomegaly and splenomegaly are typical. Another frequent finding are lymphadenopathies. It is less uncommonthe cutaneous hyperpigmentation (black disease), pulmonary affectation, larynx, esophagus, stomach, small intestine and bone marrow.20 Typical blood test alterationsare: anaemia, thrombocytopenia, leucopenia and hypergammaglobulinemia. Our patient presented an indolenthepatosplenomegaly of 20 cm found in a control of abdominal CT scan in the follow-up of a testicular seminomapreviously operated.

He was not presenting lymphadenopaties, perspiration, loss of weight, anorexia or fever. Blood tests revealed pancytopeniawithout hypergammaglobulinemia.

DIAGNOSIS
Diagnosis of the patients who present co-infection VL/HIV is difficult since a positive Leishmania serology is presentin 40-50% of cases.9 It is therefore recommended by performing two serological test. Title of antibodies in patient HIV + with important decrease of lymphocytes CD4 + is 50 times lower that in patient HIV negatives. Determination of antibodies opposite to the Leishmaniaby means of test of direct agglutination presents a sensibility of 72% and a specificity of 94%.19 Detection of Leishmania DNA by means of PCR has proved to be useful to see the response to the treatment and presents a sensibility between 82-100% when it is obtained of bone marrow21,22 and 72-100% when are obtained from peripheral blood.19 Splenic aspirate is not recommended because of the risk of bleeding. Sensibility of bone marrow aspirate is similar (50-100%)9 and does not present the above mentioned risk whereby it is indicated.

Figure 1
Hepatosplenomegaly of 20 cm

click to enlarge
Figure 2
Leishmania in White pulp (HaE 4x)

click to enlarge

 

A new test of agglutination designed to detect the antigen of Leishmania in urine (Katex) has a sensibility that ranges between 85-100% and a specificity of 96%.23,24 Positivity appears to be related to the degree of parasitemia. It is a technology adapted for the monitoring of the response to treatment, so that when the test is negative the possibility of relapse repeatedly is 5% at six months.

However, direct visualization of amastigotes in clinical samples is the gold standard. Sensibility of the detection of amastigotes in spleen, bone marrow, and lymph node is 95%, 55-97%, and 60% respectively.2 In our case, the study of bone marrow did not show atipia in any of the series, presenting a plasmacytosis > 6% with absence of parasites intracellulares. None biopsies were performed since lymphadenomagalies were not observed. Diagnosis was established after the completion of open splenectomy visualization of amastigotes in the spleen.

TREATMENT
The cornerstone of treatment have been the pentavalent antimony, except in India, Bihar siege and Southeastern Europe where the efficiency of the treatment has diminished to 35%.25 Other treatments that have been proved without success in these areas (India) has been pentamidine, due to his poor efficiency and side effects. Paromomycin seems to be an effective alternative without high costs, who presents according to the studies an efficiency of 93% with dose of 16 mgr/kg/day during 21 days26 or of 97% with dose of 20 mgr/kg/day during 21 days.27 Miltefosine (50-100 mgr/day for 28 days) is the first agent who has used for oral route for the treatment of the VL in patients with resistances to the pentavalent antimonyes28 with an efficiency of 94%.29 It’s contraindicated in pregnant women.

Nowadays, Liposomal amphotericin B is used with high efficiency and minor number of side effects in short rate (1-3 mgr/kg/5 days or 5mgr/kg /1 dose) with an efficiency of 93-97 %, reducing this way the hospital stay. This therapy is not applicable to developing countries for the high cost that it supposes.30,31,32

Most patients respond to treatment in the first 7-10 days presenting a favorable response of 90% to 2 weeks. 5-10% of patients do not respond or die. Patients who present co-infection VL-HIV present major degree of parasitemia, major number of recurrences after leaving the treatment and worse response to the treatment. Still there is no consensus on treatment duration in this group of patients when there is a good response to the anti-retroviral therapy or when a reference of the VL takes place. Mortality associated with not treated VL ranges between 75-95%.

CONCLUSIONS
HAART is the best strategy for the prevention of opportunistic infections in HIV patients. Nevertheless, prophylaxis is still necessary in countries with limited economic resources and also in developed countries. Diagnosis is usually made by directly visualizing parasites in a bone marrow aspirate so splenectomy as a method of diagnosis of VL in HIV patient must be reserved as last resource.

The Authors declare no financial support. The Authors declare that written consent was obtained from the patient.

Figure 3
Leishmania in Cytoplasm of Macrophage

click to enlarge

REFERENCES

1. Alvar, J., S. Yactayo, and C. Bern. 2006. Leishmaniasis and poverty. Trends Parasitol. 22:552–557

2. Reithinger, R., JC. Dujardin, H. Louzir, C. Pirmez, B. Alexander, and S. Brooker. 2007. Cutaneous leishmaniasis. Lancet Infect. Dis. 7:581–596

3. World Health Organization. 1998. Life in twenty first century: a vision for all. World Health Report. World Health Organization, Geneva, Switzerland

4. TV Piscopo, A C Mallia. Leishmaniasis Review. Postgrad Med J. 2006; 82:649–657.

5. Desjeux, P., and J. Alvar. 2003. Leishmania/HIV co-infections: epidemiology in Europe. Ann. Trop. Med. Parasitol. 97 (Suppl. 1):3–15

6. WHO. 2000. Leishmania/HIV co-infection in southwestern Europe 1990– 1998: restrospective analysis of 965 cases, p. 14, vol. WHO/LEISH/2000.42. World Health Organization, Geneva, Switzerland

7. H Pickering, R Bethune, IA Eyre-Brook. Diagnostic splenectomy for visceral Leishmaniasis. On-line Case Report. Ann R Coll Surg Engl. 2009; 91

8. de la Loma, A., J. Alvar, E. Martinez Galiano, J. Blazquez, A. Alcala Munoz, and R. Najera. 1985. Leishmaniasis or AIDS? Trans. R. Soc. Trop. Med. Hyg. 79:421–422.

9. Alvar, J., C. Canavate, B. Gutierrez-Solar, M. Jimenez, F. Laguna, R. Lopez-Velez, et al. 1997. Leishmania and human immunodeficiency virus coinfection: the first 10 years. Clin. Microbiol. Rev. 10:298–319.

10. Lopez-Velez, R., J. A. Perez-Molina, A. Guerrero, F. Baquero, J. Villarrubia, L. Escribano, C. Bellas, et al. 1998. Clinicoepidemiologic characteristics, prognostic factors, and survival analysis of patients coinfected with human immunodeficiency virus and Leishmania in an area of Madrid, Spain. Am. J. Trop. Med. Hyg. 58:436–443

11. Pintado, V., P. Martin-Rabadan, M. L. Rivera, S. Moreno, and E. Bouza. 2001. Visceral leishmaniasis in human immunodeficiency virus (HIV)-infected and non-HIV-infected patients. A comparative study. Medicine (Baltimore).

12. WHO. 1997. Leishmania/HIV co-infection. Epidemiological analysis of 692 restrospective cases. Wkly. Epidemiol. Rec. 72:49–54.

13. Lyons, S., H. Veeken, and J. Long. 2003. Visceral leishmaniasis and HIV in Tigray, Ethiopia. Trop. Med. Int. Health. 8:733–739.

14. Bora, D. 1999. Epidemiology of visceral leishmaniasis in India. Natl. Med. J. India. 12:62–68.

15. Cruz, I., M. A. Morales, I. Noguer, A. Rodriguez, and J. Alvar. 2002. Leishmania in discarded syringes from intravenous drug users. Lancet. 359:1124–1125

16. Pineda, J. A., J. Macias, F. Morillas, J. Fernandez-Ochoa, J. Cara, R. de La Rosa, et al. 2001. Evidence of increased risk for Leishmania Infantum infection among HIV-seronegative intravenous drug users from southern Spain. Eur. J. Clin. Microbiol. Infect. Dis. 20:354–357.

17. Pineda, J. A., J. Martin-Sanchez, J. Macias, and F. Morillas. 2002. Leishmania spp. infection in injecting drug users. Lancet. 360:950–951

18. J Alvar, Pilar Aparicio , Abraham Aseffa, Margriet Den Boer, Carmen Cañavate, Jean-Pierre Dedet et al. The Relationship between Leishmaniasis and AIDS: the Second 10 Years. Clinical Microbiology Reviews, Apr. 2008, p.334–359

19. Zijlstra EE, El-Hassan AM. Visceral leishmaniasis. Trans Roy Soc Trop Med Hyg. 2001; 95(Suppl 1):S27–58.

20. Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 6th edn. Elsevier. 2005:2428–2442

21. Cruz, I., C. Canavate, J. M. Rubio, M. A. Morales, C. Chicharro, F. Laguna, et al. 2002. A nested polymerase chain reaction (Ln-PCR) for diagnosing and monitoring Leishmania infantum infection in patients co-infected with human immunodeficiency virus. Trans. R. Soc. Trop. Med. Hyg. 96(Suppl. 1):S185–S189

22. Lachaud, L., J. Dereure, E. Chabbert, J. Reynes, J. M. Mauboussin, E.Oziol, et al . 2000. Optimized PCR using patient blood samples for diagnosis and follow-up of visceral leishmaniasis, with special reference to AIDS patients. J. Clin. Microbiol. 38:236–240.

23. Riera, C., R. Fisa, P. Lopez, E. Ribera, J. Carrio, V. Falco, et al. 2004. Evaluation of a latex agglutination test (KAtex) for detection of Leishmania antigen in urine of patients with HIV-Leishmania coinfection: value in diagnosis and post-treatment followup. Eur. J. Clin. Microbiol. Infect. Dis. 23:899–904.

24. Vilaplana, C., S. Blanco, J. Dominguez, M. Gimenez, V. Ausina, C. Tural, et al. 2004. Noninvasive method for diagnosis of visceral leishmaniasisby a latex agglutination test for detection of antigens in urine samples. J. Clin. Microbiol. 42:1853–1854.

25. Murray HW, Berman JD, Davies CR, Saravia NG. Advances in Leishmaniasis. Lancet. 2005;366: 1561-77

26. Thakur CP, Kanyok TP, Pandey AK, Shinga GP, Messick C, Olliiaro P. Treatment of visceral leishmaniasis with injectable paromomycin (aminosidine). An open-label randomized phase-II clinical study. Trans R Soc Trop Med Hyg. 2000; 94: 432–33.

27. Jha TK, Olliaro P, Thakur CP,Kanyok TP, Singhania BL, Singh U, et al. Randomised controlled trial of aminosidine (paromomycin) v sodium stibogluconate for treating visceral leishmaniasis in North Bihar, India. BMJ. 1998; 316:1200–05.

28. Guerin PJ, Olliaro P, Sundar S, Boelaert M, Croft SL, Desjeux P et al. Visceral leishmaniasis: current status of control, diagnosis, and treatment, and a proposed research and development agenda. Lancet Infect Dis. 2002; 2:494–501

29. Sundar S, Jha TK, Thakur CP, Juergen E, Herbert S, Christina F, et al. Oral miltefosine for Indian visceral leishmaniasis. N Engl J Med. 2002; 347:1739–46 30. Murray HW. Progress in treatment of a neglected disease: visceral leishmaniasis. Expert Rev Anti-infect Ther. 2004; 2:279–92

31. Sundar S, Mehta H, Sures AV, Singh SP, Rai M, Murray HW. Amphotericin B treatment for Indian visceral leishmaniasis: conventional vs. lipid-formulations. Clin Infect Dis. 2004; 38:377–83.

32. Sundar S, Jha TK, Thakur CP, Mishra M, Singh VP, Buffels R. Single-dose liposomal amphotericin B in the treatment of visceral leishmaniasis in India: a multicenter study. Clin Infect Dis. 2003; 37:800–04.



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Figure 1:

Hepatosplenomegaly of 20 cm

Figure 2:

Leishmania in White pulp (HaE 4x)

Figure 3:

Leishmania in Cytoplasm of Macrophage