Visceral leishmaniasis presenting as haemophagocytic lymphohistiocytosis

Abstract

A 53-year-old man presented with a number of hospital admissions for investigation of fever of unknown origin. He became gradually weaker with significant weight loss, pancytopenia and progressive splenomegaly over a 6-month period of extensive investigation. This was undertaken at different NHS hospitals with involvement of multiple medical specialists. Clinical criteria for haemophagocytic lymphohistiocytosis were met. Following investigation, this was felt likely secondary to a low-grade lymphoma of the spleen, necessitating splenectomy for diagnostic and therapeutic purposes. Ultimately, this risky surgical procedure was avoided when positive L eishmania serology led to successful treatment with amphotericin B.

Background

Haemophagocytic lymphohistiocytosis (HLH) encompasses a wide variety of disorders characterised by immune dysregulation causing an uncontrolled hyperinflammatory response. Visceral leishmaniasis is a chronic and potentially fatal disease caused by protozoan parasites, classically presenting with hepatosplenomegaly, fever, fatigue, weight loss and anaemia. There are numerous reports associating it as a causative infection in secondary HLH.^{1 2} It remains difficult to diagnose without a high index of suspicion.

Case presentation

A 53-year-old UK resident of Caribbean ethnicity was investigated for recurrent fevers associated with pancytopenia, weight loss and progressive splenomegaly. Previous medical, drug and social history were unremarkable aside from a holiday to Benicàssim, Castellõn, Spain 2 years prior. The fevers were refractory to first-line and second-line intravenous broad-spectrum antibiotic treatment for neutropenic sepsis. Investigations took place over a number of months, initially in the primary care setting and subsequently as an inpatient with outpatient follow-up at two different National Health Service hospitals. Infectious diseases, haematology, oncology and rheumatology subspecialties were involved at each site.

Investigations

The full blood count showed a white cell count of 2.2×10⁹/L, haemoglobin 97 g/L and platelets 119×10⁹/L. The ferritin was significantly elevated at 2500 ng/mL with a transferrin saturation of 7%. The C reactive protein was 50 mg/L, lactate dehydrogenase 250 U/L and erythrocyte sedimentation rate >120 mm/hour. The renal, liver and thyroid functions were all within normal range for age. Markers of haemolysis including the direct Coombs test were negative. Immunoglobulin(Ig)G was markedly elevated at 59 g/L (polyclonal). These tests were all suggestive of an underlying inflammatory response but with a recurrently negative septic screen and an absence of infective focus. A cause could not be established with extensive infectious and autoimmune testing including viral Polymerase Chain Reaction(PCR)/antigen testing, tuberculosis and malaria screen. Triglycerides (2.6 mmol/L) and soluble CD25 (5444 pg/mL) were both elevated. Other than the mild pancytopenia, the peripheral blood film was unremarkable. Over three months, two subsequent bone marrow biopsies were both normal, including immunophenotying and cytogenetic analysis, with a reactive plasma and T cell infiltrate. Notably, there was no evidence of haemophagocytosis or leishmania amastigotes. A CT scan showed 15 cm splenomegaly, which was diffusely metabolically active (standardised uptake value (SUV) 7.2) on subsequent PET scan with no lymphadenopathy. A later MRI scan showed splenomegaly of 19 cm with ill-defined low T2 signal and non-enhancement peripherally within the spleen.

Differential diagnosis

HLH comprises a group of related disease entities encompassing primary familial and secondary causes. The clinical phenomena result from excessive activation of immune cells including macrophages and cytotoxic T cells. Uncontrolled immune activation is associated with dysregulated natural killer and T cell activity resulting in loss of normal feedback regulation of activated macrophages.³ The pathological hallmark of HLH is haemophagocytosis, although this may not be seen in early presentation of secondary cases and is not an essential requirement for diagnosis. Hypercytokinaemia (commonly interferon gamma, tumour necrosis factor (TNF) alpha and Interleukins, eg, IL-6) is likely to be the mediator of systemic tissue damage.³

Diagnostic criteria are based on the HLH 2004 Study.⁴ Secondary causes include infectious, metabolic, malignant or autoimmune conditions.⁵ In secondary HLH, the mechanism by which the trigger causes immune dysregulation, and the predispositions to this occurring, are incompletely understood. Investigation of the underlying cause of such a presentation is hence challenging due to its cross-specialty nature and relative rarity, particularly in an increasingly subspecialised secondary care setting.

The diagnostic difficulty is that a number of medical presentations will share clinical features with HLH, some of which can also be potential underlying causes. Classically, liver failure and sepsis have some overlap. In practice, the finding of significantly elevated ferritin (>10 000 ng/mL) is specific for HLH and is diagnostically helpful.⁶ The H-score has been developed to assist clinicians in diagnosis of reactive haemophagocytic syndromes.⁷ Regardless of aetiology, HLH is associated with high morbidity and mortality.

Pancytopenia will rightly prompt investigation into underlying malignancy, particularly haematological. In the absence of a clear cause of cytopenias, HLH must be considered. In cases meeting diagnostic criteria, screening for secondary causes should be based on clinical assessment and perceived risk, for example, travel history. A useful review of differential diagnoses to consider can be found in the referenced article.⁵

Treatment

The patient was treated empirically on the basis of serological tests suggestive of leishmaniasis. (Immunofluorescence—(Leishmania IFA IgG, Vircell) IgG antibodies 1280, ELISA—IgG Leishmania infantum (Novagnost, Siemens) IgG antibodies 29.9 U/mL.)

He received a 5-day initial course of intravenous Ambisome at a dose of 3 mg/kg with a further single dose at day 11 and day 21 as per international consensus guidance.⁸

Outcome and follow-up

Within 1 month of treatment completion, the symptoms of fatigue had resolved, the blood count had returned to normal and the spleen was no longer palpable. Additionally, the patient gained 5 kg of weight and felt ‘Great’.

Discussion

Visceral leishmaniasis is a potentially life-threatening systemic protozoan disease in which L eishmania parasites disseminate throughout the reticuloendothelial system.⁹ It is transmitted by phlebotomine sandflies. Areas of the Mediterranean basin including southern Spain are endemic with Leishmania infantum subspecies as a recognised pathogen causing visceral disease.⁸ Stereotypical disease manifestations include fever, weight loss, hepatosplenomegaly and pancytopenia.⁹ Hypergammaglobulinaemia is also classical.¹⁰ Onset of illness can be abrupt or gradual with a typical incubation period of weeks to months. Although rare, cases have been described in short-term travellers. Underlying immunosuppression is a strong risk factor,^{8 11} particularly in cases of delayed presentation, where reactivation of latent disease is suspected. Our patient was HIV negative with no usage of immune suppressive medication and no evidence of malignancy or autoimmune disease on extensive screening. He also had unsuppressed immunoglobulins and normal lymphocyte subsets.

This case was notable for the absence of Leishmania in the usual diagnostic sites, including blood and bone marrow,⁸ even in spite of the symptomatology and associated pancytopenia. This was confirmed subsequently at a tertiary reference laboratory. Without associated lymphadenopathy or radiological liver abnormality the diagnostic focus was the enlarged spleen. This is a notoriously dangerous site to biopsy due to the perceived associated haemorrhagic risk and hence splenectomy is often preferred as a combined diagnostic and potential therapeutic modality in cases of uncertainty. The serological positivity, although not fully diagnostic, was suggestive enough in the presence of classical clinical features, to justify treatment. The subsequent response was highly supportive of the inferred diagnosis. PCR was not performed due to a lack of clinical suspicion for leishmaniasis. This test has a very high sensitivity and can be performed on peripheral blood with a good diagnostic yield in the presence of clinical suspicion. The test, although costly, may save significant healthcare resource by providing a rapid and specific diagnosis by which treatment can be targeted.¹²

A retrospective review of cases treated in the UK reported a median time of six months from report of first symptom to diagnosis,¹¹ highlighting the diagnostic difficulty. There have been reported cases with positive splenic biopsy but absence of bone marrow leishmaniasis. In a prospective study of 50 adult patients with visceral leishmaniasis in Mymensingh, Bangladesh, splenic and bone marrow aspiration was done simultaneously in all cases to compare the sensitivity of both the procedures.¹³ The authors concluded that splenic aspiration was a more sensitive procedure than bone marrow aspiration. They reported L eishmania bodies in 90% of splenic aspirates as compared with 72% positivity of bone marrow aspirates.

Whilst there is a well-documented association between HLH and leishmaniasis, this case is unusual due to the lack of L eishmania amastigotes on several bone marrow examinations. The case was also unique with regard to the delayed presentation of presumed latent disease acquired years prior to presentation without presence of an immunosuppressive trigger.

Patient’s perspective.

This illness started to take effect in March 2018 when I first noticed increased tiredness at the end of the working day. This developed into a influenza like feeling for weeks on end, until I ended up being admitted with sepsis and other infections.

After my release and aftercare in the summer, my doctor advised me, after he received my blood test, to admit myself into hospital again via A&E. This illness crippled my body for 9 months.

Learning points.

• Haemophagocytic lymphohistiocytosis is an important differential to consider in cases of fever of unknown origin due to the high associated morbidity in untreated cases.

• Investigation of secondary causes should be guided by clinical suspicion but should be thorough and methodical in order not to miss atypical presentations.

• Complex cases with multispecialty involvement highlight a potential ‘ownership’ flaw where patients fall between services. There is a requirement for good interspecialty communication to ensure effective investigation and management without undue overlap.