Clinical features of visceral leishmaniasis

VANESSA YARDLEY: Welcome to step 2.2. This step will look at the key symptoms of VL and possible complications that may be seen alongside a VL infection. PKDL will also be discussed with an emphasis on the different presentations of this manifestation of Leishmania donovani. Leishmaniasis is often referred to as a spectrum of disease, meaning that it presents in a variety of ways, depending upon the species of Leishmania and the host’s immune response to that parasite. For example, some forms will self cure, such as cutaneous leishmaniasis caused by Leishmania major. And some will cause a fatal infection, namely Leishmania donovani which causes visceral leishmaniasis.

The time between being infected from the bite of the sand fly to the appearance of VL symptoms can range from a month to two years, though typically this incubation period is two to six months. Symptoms may appear slowly or quickly. And importantly, people can be infected and never show clinical signs. These are often referred to as asymptomatic and it is generally accepted that there are a higher proportion of asymptomatic VL infections compared to clinical cases. For example, in India in 2010 a study estimated that for every child under five with clinical VL, there were over six who were infected but asymptomatic. In adults this proportion was 18 to one.

This ratio is likely to vary from country to country and from season to season. And the role of infected asymptomatic individuals in the transmission dynamics of VL is not clearly understood. The general term visceral leishmaniasis encompasses a broad spectrum of severity and manifestations with a chronic, subacute, or acute onset and an incubation period of weeks, months, or sometimes years. In contrast, the term kala-azar typically is reserved for advanced, life-threatening disease. Although kala-azar actually means darkening of the skin, this is, in fact uncommon. The classic manifestations of advanced disease include prolonged fever which often undulates with peaks later in the day, and cachexia - malnutrition being a risk factor for and a consequence of visceral leishmaniasis.

The majority of VL patients will have splenomegaly. Palpation of the spleen is key, as this is used to decide whether to perform a splenic aspirate or not. A rare low percentage will not present with an enlarged spleen, but they will have a fever and a number of other concomitant symptoms, such as severe weight loss, anaemia, coughing, and diarrhoea. Now we will show you a short video of a patient in India with suspected visceral leishmaniasis. The clinician will determine the size of the spleen by palpation.

Hepatomegaly is much less commonly encountered than splenomegaly. it is evaluated by palpating below the right margin of the ribs. And there may be other clinical signs of liver involvement such as jaundice. After cure the liver usually returns to its normal size.

As well as the classic symptoms of VL, other clinical signs of infection can include anaemia - severe anaemia can lead to heart failure. There is often a reduction in neutrophils and white blood cells and platelets, and an excess of gamma globulin in the blood, usually referred to as hypergammaglobulinemia. This mostly consists of IgG from polyclonal B cell activation. There may also be an increase of lymphocytes and monocytes in the blood. Patients may also have a persistent cough that could indicate an additional respiratory infection. All of these symptoms are often associated with VL and their presence at admissions should be noted. There are often atypical symptoms of VL infection which may be seen alongside fever, splenomegaly, and weight loss.

They may be indicative of underlying complications such as co-infection or may be due to the aetiology of the disease in a particular area or population. Asymptomatic carriers may progress to clinical VL, but predicting this is not currently possible PKDL is a manifestation of Leishmania donovani infection which involves the skin and is seen after a visceral infection has been resolved, although there are anecdotal reports of PKDL occurring without any previous history of VL. PKDL typically occurs months after clinical cure with the initial appearance of plaques, nodules, and papules on the skin, each full of infected macrophages. Amastiogotes are not usually detected in liver, spleen, and bone marrow if tested. The occurrence of PKDL varies between endemic settings.

In Sudan for example, the rates of developing PKDL after VL is higher than in South Asia. And the interval between VL cure and the onset of PKDL is generally shorter in East Africa. If you’d like to learn more about PKDL, WHO have an online course specifically on PKDL. PKDL in South Asia presents differently to that seen in East Africa. It tends to occur in 10% to 20% of post VL patients up to years after the VL infection has been resolved. It frequently presents as flat macular lesions which have low numbers of amastigotes before progressing, if not treated, to papular and nodular lesions. These are full of amastigotes.

In India PKDL is rarely self-limiting and the treatment regimen is long and challenging. PKDL in Sudan, Ethiopia, and South Sudan is unique and different from PKDL in South Asia. It occurs at a much higher frequency, up to 60%, and tends to develop after a few months post VL treatment. It is often papular and begins around the mouth and then increases in number and size to cover the face.

Three grades of PKDL have been described in Sudan and have subsequently been adopted by South Sudan and Ethiopia for clinical grading.

This slide outlines grades 1 and 2. And this slide describes grade 3. There is no grading system for South Asia. But PKDL is often classified as mild, moderate, or severe.

A significant complication of VL infection is coinfection with the HIV virus. It is known that each exacerbates the other - the presence of HIV can accelerate the onset of VL symptoms, and the VL infection can help drive viral replication. These patients may also have atypical symptoms and disease presentations and the diagnostic tests used to confirm VL may not be appropriate in these cases. In India it is now policy to determine the HIV status of all VL patients.

To summarise, we can list some key things that would define a case of VL, known as the case definition. If the person is from a known VL endemic area and has had a fever for more than two weeks, VL could be the cause. Other key signs to look for are splenomegaly, weight loss, and lymphadenopathy. The presence of these signs would be sufficient to warrant a diagnostic test for VL. But other infections may also need to be ruled out at this stage as many topical and non-tropical infections can mimic kala-azar.