Hyperreactive malarial splenomegaly (HMS) is the most frequent cause of massive tropical splenomegaly in areas with a stable transmission of malaria.1  Studies on the pathogenesis of HMS suggest a critical role of aberrant immunologic response to malaria antigens after repeated infections, resulting in splenic hypertrophy, sometimes associated with secondary hypersplenism.2-6  The prognosis of untreated HMS is unfavorable with mortality of 50% in endemic areas, up to 85% in the presence of severe splenomegaly.1 

In malarious areas, the high frequency of hemoglobinopathies, such as sickle cell disease (SCD), support their protective role against Plasmodium falciparum malaria.7-9  However, in patients homozygous for sickle hemoglobin (SS), the persistence of unrecognizable P falciparum infection could trigger acute hemolytic4  events and/or recurrent vaso-occlusive crises (VOCs). Since splenomegaly is the clinical manifestation common to both diseases, HMS might be easily overlooked in SS patients in malaria-endemic countries or in SS subjects recently emigrated to Europe or North America from Africa.

Here, we describe two SCD patients recently emigrated from Africa, with large splenomegaly and hypersplenism, who were hospitalized for irregular, low-grade fever (< 38°C), anemia, and severe VOCs (Table 1). Patient 1 was a 6-year-old boy from Angola, and patient 2 was a 17-year-old girl from Nigeria. Both cases were characterized by large splenomegaly (spleen longitudinal diameter: case 1, 12 cm; case 2, 23 cm) and hypersplenism, negative search for malaria, high-titer antimalarial antibodies, and increased serum immunoglobulin M (IgM) level, compatible with HMS (Table 1). After transfusion of packed erythrocytes, both patients became positive for malaria (P falciparum), and trophozoites were found only in normal (transfused) erythrocytes, clearly distinguishable from the patients' sickled red cells (Figure 1A-B; Table 1). The patients were treated, respectively, with halofantrine at standard dosage in patient 1 and artemether at standard dosage for 5 days followed by a single standard-dose pyrimethamine-sulphametopyrazine in patient 2. In a few days, the fever disappeared and blood films became negative with resolution of the clinical manifestations. After antimalarial treatment in patient 1, the IgM level became normal, abdominal pain disappeared, and spleen size reduced to 9.5 cm; whereas in patient 2, despite successful antimalarial treatment, the decrease in IgM levels, and the marked reduction in spleen size (13 cm polo-polar diameter), the chronic hemolytic anemia related to SCD still required transfusion. Then, the patient had a splenectomy.

Table 1.

Hematologic and biochemical data from patients with SCD and HMS.



 

Baseline
 

10 d
 

16 d AMT*
 

30 d
 

107 d
 
Case no. 1      
   Hct, %   18.3   28.2   29.7   21.8   38.9  
   Hb, g/L   49   86   95   65   121  
   HbS, %   96.6   ND   ND   ND   ND  
   MCHC, g/L   269   305   318   298   312  
   PLTs, cells × 109/L   182   216   113   152   217  
   WBC cells × 109/L   29.7   14.8   6.8   34.6   15.9  
   QBC   Negative   Negative   Positive   Negative   Negative  
   Blood film   Negative   Negative   Positive   Negative   Negative  
   IgM, g/L  30   ND   ND   21   13  
   Ab anti-P falciparum  1/5120   ND   ND   ND   ND  
Case no. 2      
   Hct, %   19   31   24   26   31  
   Hb, g/L   59   100   82   84   110  
   HbS, %   84   28   47   29   ND  
   MCHC, g/L   320   310   310   300   320  
   PLTs, cells × 109/L   107   112   176   154   419  
   WBC cells × 109/L   6.4   11.5   8.5   9.9   3.6  
   Tbil, mg/dL   4   3.1   2.4   2   1.9  
   IgM, g/L  400   430   280   23   37  
   QBC   ND   Positive   Positive   Negative   ND  
   Blood film   Negative   Positive   Positive   Negative   ND  
   Ab anti-P falciparum
 
ND
 
1/20 480
 
ND
 
ND
 
ND
 


 

Baseline
 

10 d
 

16 d AMT*
 

30 d
 

107 d
 
Case no. 1      
   Hct, %   18.3   28.2   29.7   21.8   38.9  
   Hb, g/L   49   86   95   65   121  
   HbS, %   96.6   ND   ND   ND   ND  
   MCHC, g/L   269   305   318   298   312  
   PLTs, cells × 109/L   182   216   113   152   217  
   WBC cells × 109/L   29.7   14.8   6.8   34.6   15.9  
   QBC   Negative   Negative   Positive   Negative   Negative  
   Blood film   Negative   Negative   Positive   Negative   Negative  
   IgM, g/L  30   ND   ND   21   13  
   Ab anti-P falciparum  1/5120   ND   ND   ND   ND  
Case no. 2      
   Hct, %   19   31   24   26   31  
   Hb, g/L   59   100   82   84   110  
   HbS, %   84   28   47   29   ND  
   MCHC, g/L   320   310   310   300   320  
   PLTs, cells × 109/L   107   112   176   154   419  
   WBC cells × 109/L   6.4   11.5   8.5   9.9   3.6  
   Tbil, mg/dL   4   3.1   2.4   2   1.9  
   IgM, g/L  400   430   280   23   37  
   QBC   ND   Positive   Positive   Negative   ND  
   Blood film   Negative   Positive   Positive   Negative   ND  
   Ab anti-P falciparum
 
ND
 
1/20 480
 
ND
 
ND
 
ND
 

Hct indicates hematocrit; Hb, hemoglobin; ND, not determined; HbS, hemoglobin S; MCHC, mean corpuscular hemoglobin concentration; PLTs, platelets; WBC, white blood cells; QBC, quantitative buffy coat; and Ab anti–P falciparum, positive > 1/80.

*

Starting day for antimalarial treatment

IgM (normal values < 25 g/L)

Figure 1.

Patient-blood smears. (A) case no. 1; (B) case no. 2. (A-B) Blood smears showing the patients' abnormal sickle cells, the transfused normal erythrocytes, and rare normal red cells with Plasmodium falciparum (arrows; Giemsa, original magnification × 1000, using a Plan-Apochromat 63×/1.4 NA oil objective, on an Olympus Provis AX70 microscope [Olympus, Tokyo, Japan]). Images were captured with a Nikon Coolpix 4500 digital camera (Nikon, Tokyo, Japan) and processed with Nikon View 5 Coolpix 5.1.3 (Nikon) and Adobe Photoshop 6.0 (Adobe Systems, San Jose, CA).

Figure 1.

Patient-blood smears. (A) case no. 1; (B) case no. 2. (A-B) Blood smears showing the patients' abnormal sickle cells, the transfused normal erythrocytes, and rare normal red cells with Plasmodium falciparum (arrows; Giemsa, original magnification × 1000, using a Plan-Apochromat 63×/1.4 NA oil objective, on an Olympus Provis AX70 microscope [Olympus, Tokyo, Japan]). Images were captured with a Nikon Coolpix 4500 digital camera (Nikon, Tokyo, Japan) and processed with Nikon View 5 Coolpix 5.1.3 (Nikon) and Adobe Photoshop 6.0 (Adobe Systems, San Jose, CA).

Here, we show that plasmodia may be undetectable in homozygous SCD patients, most likely because spleen clearance of parasitized sickled red blood cells (RBCs)10  maintains the peripheral parasitemia at levels too low to be detected, even by sensitive methods. Otherwise, malaria itself may trigger hemolytic episodes, and the persistence of an untreated low parasitemia may lead to the development of a chronic malaria, ending up in a true hyperreactive malarial splenomegaly, which is a life-threatening disorder per se.

We believe that the management of SCD patients in and from malaria-endemic areas should take into account the possibility of an undetected low parasitemia and of concurrent HMS, which may worsen the SCD chronic hemolytic anemia and/or increase the frequency of severe VOCs.

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