A neglected cause of lymphadenopathy

Case

59 year old male who is a known case of HIV and previously

treated for visceral leishmaniasis. Presented to HIV clinic for
routine check up, with the main complaint of generalised
lethargy.
• On examination
– cervical and inguinal lymphadenopathy
•approximately 2cm in size in both areas

•hepatosplenomegaly: distended but soft and non tender

• Also of note was a recent weight loss and a long-standing dry cough

• No reported fever or night sweats

• No other positive findings were of note

• Drug History
– Symtuza
– NKDA

Patient was directly admitted for further investigations

– US guided lymph node biopsy
– CT thorax, abdomen and pelvis
– Bone marrow aspiration
Pancytopenia was also noted in his blood work
– WCC 1.02
– Neutrophils 0.58
– Platelets 57
– Hb 7
2 units of RCC were subsequently transfused after which Hb was
still 7.7 and another unit of RCC was transfused.
In view of his past history of visceral leishmania and the tell tale signs
and symptoms he was exhibiting, patient was started on
Amphotericin B.
CT Abdomen & Pelvis
• Thorax:
– 10mm nodule in the anterior segment of the right upper lobe
– Enlarged lymph nodes in anterior mediastinum, supradiaphramatically
– Circumferential wall thickening of distal oesophagus with few surrounding lymph
nodes
• Abdomen
– Hepatosplenomegaly with hypodense lesions within both structures
– Dilated portal and hepatic veins
– Moderate ascites
– Liver hilar, perigastric, coeliac, mesenteric, aortocaval and bilateral inguinal
lymphadenopathy
– Cholecyctitis- 2 calculi in gallbladder neck
US guided biopsy:
Biopsy of enlarged lymph node in the left groin
– granulomatous infiltrate accompanied by lymphocytes and plasma cells.
Numerous leishmania amastigotes with no evidence of neoplasia.

Bone marrow aspiration:

Decreased iron stores with no ring sideroblasts, very few fragments present.
Marrow is heavily infiltrated by Leishman Donovan bodies

Leishmania Spp PCR Urine:

Detected
 As the diagnosis was now re-confirmed, the patient was
thus continued on Amphotericin B with appointments to
continue treatment in hospital as an outpatient.

Case planned to be discussed at MDT meeting in view of

multiple findings on CT TAP
Leishmaniasis

• 3 main forms of leishmaniases:

– visceral (commonly fatal without treatment)
– cutaneous (the most common, usually causing skin ulcers)
– mucocutaneous (affecting mouth, nose and throat)
• The protozoan parasites causing Leishmaniasis are transmitted by the bite of
infected sandfly
• The disease is associated with malnutrition, population displacement, poor
housing and immunosuppression.
• An estimated 700 000 to 1 million new cases occur annually
•Visceral leishmaniasis (VL) is a zoonotic vector-borne
disease caused by the Leishmania donovani protozoa
complex
•Highly endemic in Iran, Somalia, Sudan and Yemen.
Common in the tropics, subtropics, and the Mediterranean.
•Complex parasite–host interactions, predispose certain
individuals to developing the disease or to controlling the
infection hence influencing a spectrum of clinical
manifestations ranging from asymptomatic to fatal visceral
infections.
In non-endemic areas, VL is mostly opportunistic, with up to
70% adult cases related to HIV co-infection. The greatest
prevalence of co-infection in non-endemic areas is in the
Mediterranean area. Atypical presentations of VL are reported
in HIV patients (WHO, 2007).
The numbers of leishmaniasis cases are increasing worldwide
due to:
• lack of vaccines
• difficulties in controlling vectors
• increasing number of parasites resistance to chemotherapy.
Clinical Presentation
• Fever & night sweats
• Weight loss
• Hepatosplenomegaly
• Pancytopenia
• Hypergammaglobulinemia
• Skin darkening
Patients typically appear cachectic with abdominal
distention due to massive hepatospenomegaly. Jaundice
is rarely seen and is considered a bad prognosticator.
In the immunosuppressed:
• gastrointestinal and respiratory involvement
Investigations
• Parasites can be detected through direct evidence in the form of amastigotes
(differentiated promastigotes in the phagosome) in tissue; from peripheral
blood, bone marrow, liver or splenic aspirates
• Immunodiagnostic serologic tests
– Indirect fluorescent antibody (IFA) test, which is 80-100% sensitive in
patients who are not co-infected with HIV.
– ELISA can be combined with IFA and Western blot to increase sensitivity
and specificity. PCR is being used more frequently; it is more accurate in
determining new-onset leishmaniasis as compared to serum tests (92-99%
sensitivity; 100% specificity)
– Serologic tests such as isoenzyme or monoclonal antibody analysis are not
well established.
Investigations: Routine Labs
• CBC:
– normocytic, normochromic anaemia
– leukopenia; reduced neutrophils, monocytosis and lymphocytosis
– thrombocytopenia
• LFT:
– mild increase in ALP, AST and ALT
• Hypogammaglobulinemia, immune complexes and rheumatoid
factors are present in most patients
• Definitive diagnosis of visceral leishmaniasis requires organ aspiration and
microscopic examination of tissue specimens.
• Noninvasive diagnosis by strip test detection of anti-K39 immunoglobulin (Ig)
G antibody in blood specimens obtained by fingerstick is available
• For active case detection, the recombinant K39 immunochromatographic test
(rK39 ICT) offers a simple, non-invasive and accurate test with increased
patient compliance. Reliable tests are also required to estimate actual disease
burden, track disease trends over time, improve diagnosis-treatment
algorithms and to verify disease elimination within communities
Management

Leishmaniasis is a somewhat neglected tropical disease in terms of drug

discovery and development.
Several drugs, differing in their cost, toxicity, treatment duration and
emergence of drug resistance, are used for different types of
leishmaniasis.
Recent improvements have been achieved by combination therapy,
reducing the time and cost of treatment. Nonetheless, new drugs are
still urgently needed.
Management
Treatment approach depends on host and parasite factors

•Liposomal amphotericin B (AmBisome®), which is

administered by IV infusion
•Oral agent miltefosine for treatment of cutaneous, mucosal,
and visceral leishmaniasis caused by particular Leishmania
species
Lipid formulations of Amphotericin B
improve its bioavailability and
pharmacokinetics whilst also reducing side
effects. The lipid molecules are rapidly
assimilated by hepatic macrophages, where
the parasite accumulates. Another
advantage is that smaller liposomes stay in
the blood stream longer than the free drug.
The main limitations are its high cost,
administration route and lack of stability at
high temperature.
Adapted from Visceral leishmaniasis treatment: What do we have, what do we need and how to deliver it? Freitas-Junior et al.
2012
Management
• Until now, the recommendation for treatment of a VL episode in an
HIV co-infected patient was first to consider lipid formulations of
amphotericin B, infused at a dose of 3–5 mg/kg daily or in 10
intermittent doses (on days 1–5, 10, 17, 24, 31 and 38) to a total dose
of 40 mg/kg.
• Evidence from clinical trials on the efficacy of combination therapy
(liposomal amphotericin B (L-AMB) plus miltefosine) to treat VL in
HIV co-infected patients instead of monotherapy has offered new
possibilities for case management.
• Immunosuppression is a risk factor for VL and can alter disease
presentation and management.
• Leishmania with HIV coinfection has several characteristic features:
– lower cure rates
– higher rates of drug toxicity
– higher relapse and mortality rates
• Use of an effective systemic therapy is important, as is supportive
care: therapy for malnutrition, anemia/bleeding, and intercurrent
infections. Antiretroviral therapy should be started or optimized;
appropriate use of ART may delay relapses and improve survival.
HIV infection and leishmaniasis share an immunopathological pathway
that enhances replication of both pathogens and accelerates the
progression of both VL and HIV (Tremblay et al., 1996; Alvar et al., 2008; Mock et al., 2012)
 Prevention
• No vaccines or drugs available for prevention
• The best way for travelers and susceptible people to prevent infection
is to protect themselves from sand fly bites.
– Personal protective measures include:
•minimizing nocturnal outdoor activities
•wearing protective clothing
•applying insect repellent to exposed skin
• Prevention measures must be tailored to the local setting and typically
are difficult to sustain. Control measures against sand fly vectors or
animal reservoir hosts might be effective in some settings
References

• Ramos et al. Is Visceral Leishmaniasis Different in Immunocompromised Patients Without Human

Immunodeficiency Virus? A Comparative, Multicenter Retrospective Cohort Analysis. Am J Trop Med Hyg.
2017 Oct;97(4):1127-1133. doi: 10.4269/ajtmh.16-0940. Epub 2017 Oct 10. PMID: 29016284; PMCID:
PMC5637592.
• Sundar et al. Noninvasive Management of Indian Visceral Leishmaniasis: Clinical Application of Diagnosis by
K39 Antigen Strip Testing at a Kala-azar Referral Unit. Clinical Infectious Diseases, Volume 35, Issue 5, 1
September 2002, Pages 581–586
• Singh O.P., Sundar S. Developments in diagnosis of visceral Leishmaniasis in the elimination era. J. Parasitol.
Res., 2015 (2015), p. 239469
• Lucio H. Freitas-Junior, Eric Chatelain, Helena Andrade Kim, Jair L. Siqueira-Neto. Visceral leishmaniasis
treatment: What do we have, what do we need and how to deliver it? International Journal for Parasitology:
Drugs and Drug Resistance 2 (2012) 11-19
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