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Do you know which disease fits this month’s case? Then test your knowledge in the quiz below!

Can you explain the mild thrombocytopenia in this patient? Idiopathic thrombocytopenic purpura (ITP)
Malaria caused by Plasmodium vivax infection
Rheumatoid arthritis
Pneumonia

Online version of this month´s case:

Correction

It has been brought to our attention that the schizont, visible on the peripheral blood smear, is too large and contains too many merozoites for a Plasmodium malariae infection. Follow up confirmed that this was a Plasmodium vivax infection. We apologize for the confusion.

The correct answer to January´s Quiz is:

Malaria caused by Plasmodium vivax infection

Scattergrams and microscopy:

Table:

Interpretation and differential diagnosis:

The answer can be inferred from…

  • Presence of the action message ‘Difference between WNR and WDF. Check the results’, caused by differences in WBC counts from the WDF channel (9.53 x 109/L) and WNR channel (5.64 x 109/L)
  • Presence of an abnormal neutrophil population in the WDF scattergrams: increased neutrophil granularity (NEUT-GI) and two neutrophil populations in the SSC-FSC scattergram
  • Unreliable results for all WBC differential parameters, caused by the presence of the abnormal neutrophil population
  • Combination of relative neutrophilia and normal neutrophil reactivity (NEUT-RI)

Case history

A 34-year old man who frequently travels to Papua New Guinea visited his physician with a fever, nausea, headache and painful joints. Considering the man’s travel history, a complete blood count with WBC differential and reticulocyte analysis was performed to investigate a possible malaria infection.

Case results

Absolute neutrophil counts were normal but close to 95% of all WBC in the peripheral blood were classified as neutrophils indicating a relative neutrophilia. Furthermore, the Neutrophil-Granularity-Intensity (NEUT-GI) was increased while the Neutrophil-Reactivity-Intensity (NEUT-RI) was normal. Interestingly, the SSC-FSC scattergram of the WDF channel showed two neutrophil populations and the WBC count from the WDF channel was much higher than the count from the WNR channel (9.53 x 109/L compared to 5.64 x 109/L). This is indicative of nucleic acid-containing cellular inclusions in RBC, which don’t interfere with the WBC count in the WNR channel due to the strong lysis reagent. Since RBC are not completely lysed in the WDF channel, they are visible as an additional neutrophil population. The presence of this abnormal neutrophil population in the scattergram without signs of neutrophil activation (normal NEUT-RI) pointed to a P. malariae infection. The negative Delta-He and low RET-He are inflammatory signs, while a mild thrombocytopenia is common in malaria (1) but also in the alternative diagnoses. Malaria was confirmed in the peripheral blood smear, which showed the presence of parasites in the early Schizont stage.

(*Please note that Sysmex offers for XN-Class analysers a new software that triggers a flag ‘iRBC?’ (inclusions in RBC) flag in such situations. An automated correction of the WBC count and the differential is part of the algorithm.)

The following answers are incorrect for the described reasons

 

Idiopathic thrombocytopenic purpura (ITP)

ITP is an autoimmune haematological disorder in which autoantibodies against platelet antigens induce accelerated platelet destruction, leading to a reduction in peripheral blood platelets. ITP causes a characteristic purpuric rash and a tendency to bleed, for example from the nose or periodontal gums. It is difficult to distinguish ITP from other causes of thrombocytopenia so its diagnosis is a process of exclusion. Megakaryopoietic activity of the bone marrow is typically enhanced in ITP patients but it was probably normal or decreased in the presented patient (normal MPV and P-LCR values) suggesting a production problem rather than accelerated platelet destruction. In addition, ITP patients don’t have a (pseudo)neutrophilia or ineffective erythropoiesis so an ITP was highly unlikely.

Rheumatoid arthritis

A rheumatoid arthritis (RA) diagnosis was also explored because the patient had painful joints. Like ITP, RA is also an autoimmune disease; RA-associated autoantibodies affect the lining of the joint cavities (synovium) in synovial joints. Over time this causes deformation of the joints leading to serious disability when left untreated. RA affects 1.1% of women and 0.4% of men. RA is associated with an inflammatory response, which was not seen here: WBC counts were normal and lymphocyte counts were decreased here.

Underlying disease:

Malaria

Despite different treatment options malaria remains a devastating infectious disease in the tropics: Each year 100-300 million people are infected with malaria worldwide and this is fatal in approximately 627,000 patients, mainly children below the age of five in Africa (2). While malaria exists in more than 100 countries it is mainly confined to poorer tropical areas of Africa, Asia and Latin America. More than 90% of malaria cases and the great majority of malaria deaths occur in tropical Africa. Older Africans have a reduced infection risk because they develop a degree of immunity as a result of continuous exposure. Pregnant women in Africa (especially women who are pregnant for the first time) are particularly vulnerable. Malaria poses a risk to travellers as well, and emigration from endemic areas also results in an increasing incidence in non-endemic areas (3). This poses a challenge because knowledge about diagnostics and treatment of malaria is not commonplace in Europe.

Malaria is a haemoprotozoan parasitic infection transmitted primarily by the bite of an infected female Anopheles mosquito. Malaria may also be transmitted via blood transfusion or congenitally between mother and foetus but this is rare. In humans, parasites multiply exponentially in the liver and, after several developmental stages, in infected RBC. Mosquitoes ingest parasites with a blood meal upon which the parasites undergo another reproductive phase inside the mosquito before being passed on to another human host.

Malaria species

Of the four species of Plasmodium that commonly infect humans (P. falciparum, P. vivax, P. ovale and P. malariae) P. falciparum accounts for most morbidity and mortality. It is found throughout tropical Africa, Asia and Latin America. Infection with P. falciparum is not restricted to RBC of a particular age and therefore results in the highest levels of parasitaemia. P. vivax is found worldwide in tropical and some temperate zones while P. ovale occurs mainly in tropical West Africa. These infections are similar to P. vivax infections but they are usually less severe and often heal without treatment. P. malariae also occurs worldwide but has a limited, intermittent distribution. Those infected with P. malariae remain asymptomatic for a much longer period of time than those infected with P. vivax or P. ovale and recrudescence is common.

Clinical manifestations

Fever and chills are almost always present (96% of patients) and are accompanied by headache (79%), muscle pain (60%), hepatomegaly (33%), splenomegaly (28%), nausea and vomiting (23%), and abdominal cramps/diarrhoea (6%). Clinical symptoms of malaria usually occur around the time of RBC lysis with fever resulting from the release of merozoites, malarial pigment and protein, and cellular debris. Chills or rigors followed by high fever occur in a cyclical pattern in P. vivax, P. ovale and P. malariae infections but not in P. falciparum infections, which exhibit a continuous fever with intermittent spikes. The classical malaria paroxysm is often not observed but it consists of three phases: the ‘cold’ stage, the ‘hot’ stage and the ‘sweating’ stage. Non-immune patients experience some or all of these symptoms, while persons living in endemic areas are infected intermittently and develop partial immunity, leading to less severe symptoms.

P. falciparum infection: P. falciparum parasites mature in RBC causing surface ‘knobs’ to form, which renders the RBC inflexible and ‘sticky’. These inflexible, ‘sticky’ RBC adhere to endothelial cells of capillaries and postcapillary venules in the brain, kidneys and other organs, obstructing blood flow. In the obstructed microvasculature parasites consume glucose, cause acidaemia and release tissue necrosis factor. The capillaries subsequently become more permeable allowing leakage of protein and fluids, which results in tissue oedema, anoxia, organ damage and death. In some cases infected RBC cannot be found in peripheral blood smears because they are sequestered in the host microvasculature. Severe complications of P. falciparum infection include cerebral malaria, renal failure, pulmonary oedema, gastro-enteritis (particularly in children) and anaemia.

P. vivax and P. ovale infection: P. vivax and

Literature:

  1. Lampah DA et al. (2014): Severe Malarial Thrombocytopenia: A Risk Factor for Mortality in Papua, Indonesia. J Infect Dis: early online.
  2. World Health Organization (2013): World Malaria Report. www.who.int/malaria/publications/world_malaria_report_2013/report/en/
  3. Muentener P et al (1999): Imported malaria (1985–95): trends and perspectives. Bulletin of the World Health Organization 77: 560–565.
  4. Eckstein-Ludwig U et al (2003): Artemisinins target the SERCA of Plasmodium falciparum. Nature 424(6951): 957-961.

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