• 1.

    Bhatia KK, Crane GG, 1989. HLA heterozygosity and hyperreactive malarious splenomegaly in the Upper Watut Valley of Papua New Guinea. P N G Med J 32: 277286.

    • Search Google Scholar
    • Export Citation
  • 2.

    Fakunle YM, Onyewotu II, Greenwood BM, Mohammed I, Holborow EJ, 1978. Cryoglobulinaemia and circulating immune complexes in tropical splenomegaly syndrome. Clin Exp Immunol 31: 5558.

    • Search Google Scholar
    • Export Citation
  • 3.

    Bisoffi Z, Leoni S, Angheben A, Beltrame A, Eseme FE, Gobbi F, Lodesani C, Marocco S, Buonfrate D, 2016. Chronic malaria and hyper-reactive malarial splenomegaly: a retrospective study on the largest series observed in a non-endemic country. Malar J 15: 230.

    • Search Google Scholar
    • Export Citation
  • 4.

    Van den Ende J, van Gompel A, van den Enden E, Taelman H, Vanham G, Vervoort T, 2000. Hyperreactive malaria in expatriates retourning from sub-Saharan Africa. Trop Med Int Health 5: 607611.

    • Search Google Scholar
    • Export Citation
  • 5.

    McGregor A, Doherty T, Lowe P, Chiodini P, Newsholme W, 2015. Hyperreactive malarial splenomegaly syndrome–can the diagnostic criteria be improved? Am J Trop Med Hyg 93: 573576.

    • Search Google Scholar
    • Export Citation
  • 6.

    Mothe B, Lopez-Contreras J, Torres OH, Munoz C, Domingo P, Gurgui M, 2008. A case of hyper-reactive malarial splenomegaly. The role of rapid antigen-detecting and PCR-based tests. Infection 36: 167169.

    • Search Google Scholar
    • Export Citation
  • 7.

    Cheaveau J et al. 2018. Clinical validation of a commercial LAMP test for ruling out malaria in returning travelers: a prospective diagnostic trial. Open Forum Infect Dis 5: ofy260.

    • Search Google Scholar
    • Export Citation
  • 8.

    Ponce C et al. 2017. Diagnostic accuracy of loop-mediated isothermal amplification (LAMP) for screening patients with imported malaria in a non-endemic setting. Parasite 24: 53.

    • Search Google Scholar
    • Export Citation
  • 9.

    Cook J et al. 2015. Loop-mediated isothermal amplification (LAMP) for point-of-care detection of asymptomatic low-density malaria parasite carriers in Zanzibar. Malar J 14: 4348.

    • Search Google Scholar
    • Export Citation
  • 10.

    Puente S, Rubio JM, Subirats M, Lago M, Gonzalez-Lahoz J, Benito A, 2000. The use of PCR in the diagnosis of hyper-reactive malarial splenomegaly (HMS). Ann Trop Med Parasitol 94: 559563.

    • Search Google Scholar
    • Export Citation
  • 11.

    Fakunle YM, 1981. Tropical splenomegaly. Part 1: tropical Africa. Clin Haematol 10: 963975.

  • 12.

    Bates I, Bedu-Addo G, 1997. Review of diagnostic criteria of hyper-reactive malarial splenomegaly. Lancet 349: 1178.

  • 13.

    Fakunle YM, Greenwood BM, 1980. Mortality in tropical splenomegaly syndrome, Trans R Soc Trop Med Hyg 74: 419.

  • 14.

    Leoni S, Buonfrate D, Angheben A, Gobbi F, Bisoffi Z, 2015. The hyper-reactive malarial splenomegaly: a systematic review of the literature. Malar J 14: 185.

    • Search Google Scholar
    • Export Citation
  • 15.

    Camara B, Kantambadouno JB, Martin-Blondel G, Berry A, Alvarez M, Benoit-Vical F, Delmont J, Bouchaud O, Marchou B, 2009. Hyperreactive malarial splenomegaly: three clinical cases and literature review. Med Mal Inf 39: 2935.

    • Search Google Scholar
    • Export Citation
  • 16.

    Masfrancx D, De Munter P, Devos T, 2013. A 75-years -old missionary with fever, splenomegaly and pancytopenia. Acta Clinica Belgica 68: 225228.

    • Search Google Scholar
    • Export Citation
  • 17.

    Aidoo M, Terlouw DJ, Kolczak MS, McElroy PD, ter Kuile FO, Kariuki S, Nahlen BL, Lal AA, Udhayakumar V, 2002. Protective effects of the sickle cell gene against malaria morbidity and mortality. Lancet 359: 13111312.

    • Search Google Scholar
    • Export Citation
  • 18.

    De Franceschi L, Sada S, Andreoli A, Angheben A, Marocco S, Bisoffi Z, 2005. Sickle cell disease and hyperreactive malarial splenomegaly (HMS) in young immigrants from Africa. Blood 106: 44154417.

    • Search Google Scholar
    • Export Citation
  • 19.

    De Iaco G, Saleri N, Perandin F, Gulletta M, Ravizzola G, Manca N, Signorini L, Matteelli A, Prestini K, Castelli F, 2008. Case report: hyper-reactive malarial splenomegaly in a patient with human immunodeficiency virus. Am J Trop Med Hyg 78: 239240.

    • Search Google Scholar
    • Export Citation
  • 20.

    Puente S, Subirats M, Benito A, Rubio JM, Gonzalez-Lahoz JM, 2001. Hyperreactive malarial splenomegaly in Europeans: report of five cases. J Travel Med 8: 322324.

    • Search Google Scholar
    • Export Citation
 
 
 

 

 
 
 

 

 

 

 

 

 

Case Report: Hyperreactive Malarial Splenomegaly Syndrome Diagnosed with Loop-Mediated Isothermal Amplification and Treated with Artemisinin-Based Combination Therapy

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  • 1 Infectious Diseases Department, Centre Hospitalier Universitaire (CHU) Saint-Pierre, Brussels, Belgium;
  • | 2 Infectious Diseases, Department of Mental and Physical Health and Preventive Medicine, Università della Campania “Luigi Vanvitelli,” Naples, Italy;
  • | 3 Hematology Department, Laboratoire Hospitalier Universitaire de Bruxelles - Université Libre de Bruxelles, CHU Saint-Pierre, Brussels, Belgium

Hyperreactive malarial splenomegaly syndrome (HMSS) is a rare cause of splenomegaly in the Western world. Hyperreactive malarial splenomegaly syndrome is caused by an aberrant immunological response to chronic malaria exposure in endemic areas. Revised Fakunle’s criteria may be helpful for diagnosis: persistent splenomegaly (> 10 cm below the costal margin), increased anti-Plasmodium antibodies, increased IgM levels, exclusion of other causes of splenomegaly or malignancy, and a favorable response to antimalarial treatment. We describe the case of a 16-year-old patient, who recently arrived in Belgium from Guinea with a history of splenomegaly and B symptoms in whom HMSS diagnosis was achieved, thanks to the loop-mediated isothermal amplification method. To our knowledge, this is also the first described case treated by dihydroartemisinin/piperaquine.

CASE REPORT

A 16-year-old boy, who recently arrived in Belgium from Guinea, was referred to our tropical diseases outpatient clinic in Brussels for splenomegaly. He stated recent B symptoms, such as weakness, hypersomnia, itching after shower, and evening febrile sensation. His past medical history was notable for multiple malarial episodes and HbS heterozygosity. The physical examination revealed a soft palpable splenomegaly 6 cm below the costal margin and two infracentimetric cervical lymph nodes, without hepatomegaly. The rest of the physical examination was unremarkable.

The first laboratory test revealed normal red blood cells and white blood cells (WBC), including lymphocyte and platelet counts. There was no inflammation, or kidney or liver dysfunction. Polyclonal hypergammaglobulinemia (18 g/L, N 6–13) was observed with increased IgM (2.8 g/L, N 0.5–1.9) and IgG levels (17.6 g/L, N 7.3–15).

Serological tests were performed (Trypanosoma brucei, Leishmania donovani, Filaria spp., Schistosoma, Strongyloides, HIV, Hepatitis B, and Hepatitis C) and were all negative. An interferon gamma release assay was negative. The patient showed positive IgG for cytomegalovirus. Epstein–Barr virus showed the following serological markers: Virus capsid antigen (VCA) IgM at 3.8 U/mL (N < 1.1), VCA IgG at 184 U/mL (N < 22) with a negative Paul–Bunnell test and positive Epstein–Barr nuclear antigen (EBNA) IgG. A first panel of malaria tests was performed with a rapid diagnostic test (SD Bioline Malaria Ag P.f/ Pan; Abott, Wavre, Belgium) and thick and thin blood smears. All tests were negative. A screening for autoimmune conditions (antinuclear Ab, rheumatoid factor, and complements) was also negative and hematological investigations were normal.

Three months later, the patient presented to emergency department because of the worsening of weakness associated with fever and cough. Blood test revealed thrombocytopenia (99,000/µL) and leucopenia (total WBC 3,000/µL with 29% of atypical lymphocytes) with normal C-reactive protein. A second blood smear for malaria was performed and was negative. Hyperreactive malarial splenomegaly syndrome (HMSS) was suspected and the patient was hospitalized in infectious diseases department. Loop-mediated isothermal amplification (LAMP) method (illumigene Malaria LAMP assay by Meridian Biosciences, Cincinatti, OH) was performed as well as IgG anti-Plasmodium falciparum: LAMP was positive for the presence of P. falciparum and serology showed extremely high IgG levels (index 5,520, N < 0.8), both being in favor of HMSS diagnosis. Thick blood smear was read again by an experienced hematologist with a positive result < 0.1% parasitemia. Treatment with dihydroartemisinin/piperaquine (320/40 mg three tablets/day for 3 days) was associated with doxycycline 200 mg once a day for 6 weeks. A bone marrow biopsy and a fluorodeoxyglucose-positron emission Tomography/computed tomography (FDG-PET/CT) were performed to exclude a malignancy, showing a few P. falciparum in the bone marrow and pneumonia of the right inferior lobe on PET/CT. A treatment with amoxicillin/clavulanate was associated to antimalarial therapy. Clinical and biological evolution was rapidly favorable and patient was discharged after a few days.

One month later, spleen was clinically unpalpable; itching and B symptoms had disappeared. Two months later, hypergammaglobulinemia, including increased IgG and IgM, was completely resolved.

DISCUSSION

We present a case of a 16-year-old Guinean boy who recently arrived in Belgium and presented with splenomegaly and B symptoms. This case highlights several aspects of HMSS: the strengths and limitations of revised Fakunle’s criteria in HMSS diagnosis; the diagnostic value in HMSS of current molecular techniques such as LAMP; and the lack of guidelines for HMSS treatment in non-endemic areas.

Hyperreactive malarial splenomegaly syndrome is caused by an aberrant immunological response to chronic malaria exposure. A genetic predisposition such as human leukocyte antigen (HLA)-DR2 haplotype1 is associated with repeated exposure to malarial antigens, leading to an excessive production of polyclonal hyperimmunoglobulinemia, especially macroglobulinemia formed by IgM and/or immune complexes. The persistent clearance of those by the reticuloendothelial system causes eventually persistent and often massive splenomegaly.2 Complications are increased susceptibility to infections, pancytopenia, and splenic rupture. Mortality of the syndrome may exceed 50% if left untreated.3

Recently arrived from a highly malaria-endemic country, our young patient presented with weakness and febrile sensation, which are described as the most usual symptoms in patients with HMSS in non-endemic countries.3,4 Negative thick blood smear is often (42–100%) reported in series of HMSS,3,5,6 and when detected, parasite density is very low most of the time.3 Thick blood smear, read by an experienced hematologist, is able to detect 50 parasites/µL; a rapid test about 100–500 parasites/μL; and LAMP two parasites/µL, as is by polymerase chain reaction (PCR).7,8 Loop-mediated isothermal amplification method is a molecular technique that uses unique DNA polymerases and specially designed primers to amplify nucleic acid without thermocyclers.7 As already described, LAMP is useful to detect malaria in asymptomatic patients with very low parasitemia (submicroscopic and subclinical parasitemia).9 The use of molecular techniques for malaria diagnosis increased the yield of Plasmodium detection in HMSS.10 Detection of submicroscopic parasitemia has been proposed as a good prognosis factor for a favorable outcome after treatment.5 To our knowledge, this is the first case in which LAMP was used to diagnose HMSS. All Fakunle’s criteria11 were present in our patient: a massive splenomegaly, an extremely increased anti–P. falciparum antibody level, raised IgM titer, and a favorable clinical–immunological response to a prolonged antimalarial therapy. The lymphocyte morphological heterogeneity, the absence of lymphocyte monoclonality demonstrated by cytometry, and the normal bone marrow and peripheral blood excluded hematological malignancy (revised criteria).12 In our case, Epstein-Barr virus (EBV) infection could have explained symptoms as well as splenomegaly and polyclonal hypergammaglobulinemia, but serological markers (negative Paul–Bunnell and positive EBNA) were discrepant. Extremely increased anti–P. falciparum antibody level, normalization of the spleen and the IgM after treatment, long stay in a hyperendemic malaria area, and multiple malarial episodes in childhood added to the cluster of arguments for HMSS. Exaggerated polyclonal stimulation of B lymphocytes is one of the mechanisms initiating HMSS and led probably to falsely positive EBV VCA IgG and IgM as already reported.3,6 Anyway, given the risk of developing a severe disease with high mortality in case of reexposure, treatment would have been justified.3 Increased susceptibility to bacterial infections is a known complication of HMSS and a historically described leading cause of mortality.13 Pneumonia was incidentally detected on PET/CT: it is difficult to assess if fever was due to pneumonia or to HMSS, with pneumonia as an incidental phenomenon.

In non-endemic countries without reexposure to P. falciparum, a short antimalarial regimen may be an option to treat HMSS.3,14 We administrated dihydroartemisinin/piperaquine, which is our first-line treatment for malaria. To our knowledge, this is the first case of HMSS treated with this combination. We continued antimalarial treatment with 6 weeks of doxycycline, as most case series report long treatments.5,15 Retrospectively, considering the low risk of reexposure, a short regimen would have been probably enough.3,14,16

A potential link between HbS and HMSS has not been studied. High prevalence of HbS heterozygosity in endemic areas and its protective role against acute P. falciparum malaria (decreased rate of cerebral malaria, mortality, and hyperparasitemia) are well known.17 Hyperreactive malarial splenomegaly syndrome in patients with sickle cell disease has already been reported,18 but incidence in this particular group is not known. The presence of HbS probably does not prevent submicroscopic parasitemia and the development of HMSS, which is mostly secondary to immunological phenomena2 and not to the presence of the parasite itself.

In Table 1, we present a summary of the publications since year 2000, reporting at least one case of HMSS in adults in non-endemic countries, which represents a total of nine studies and 113 patients. Several patients were treated with ACT in one study, but precise regimen and duration were not specified.3 In nearly all studies, revised Fakunle’s criteria were the cornerstones of HMSS diagnosis and in three reports, PCR was used to confirm submicroscopic infection.5,6,19

Table 1

Review of published cases of HMSS in adults in malaria non-endemic countries

StudyCountry (study period)Patients (n), (age), country of originDiagnosis of HMSS and other special conditionsTreatmentOutcome
Van den Ende et al.4Belgium (1986–1997)49 (10–76 years), sub-Saharan AfricaFakunle 17/49Different regimens anti-Plasmodium falciparum from 1 to 7 days according to the drug (no ACT)9/49 relapse, all following reexposure
B symptoms 42/49
Positive smear 27/49
Puente et al.20Spain (1988–2000)5 (55–70 years), Equatorial Guinea and West-Central AfricaFakunleQuinine 7 days (1)5/5 cured
Hepatic biopsy 3/5 (all with lympho sinusoidal infiltration)Halofantrine 4 days (4)
Negative OMB 5/5All (5/5) + chloroquine 6–12 m
Positive smear 0/5
De Franceschi et al.18Italy (not specified)2 (6 years), Angola; (17 years), NigeriaFakunleHalofantrine + splenectomy for SCD (1)2/2 cured
Positive smear 0/2Artemeter 5 days + pyrimethamine sulfametopyrazine single dose (1)
2/2 SCD
De Iaco et al.19Italy (2004)1 (57 years), CameroonFakunleMefloquin single dose (renal impairement)Cured
Negative smear
Positive PCR
New diagnosis of HIV
Mothe et al.6Spain (not specified)1 (67 years), CameroonFakunleChloroquine 3 days + primaquine 2 weeks relapse:Cured
Negative OMBQuinine + doxycycline 1 week
Negative smear
Positive PCR
Camara et al.15France (2001–2006)3 (15–71 years), CameroonFakunleMefloquine + doxycycline for 30 days followed by choloroquine + doxycycline for other 30 days (1)3/3 cured
Negative smear 3/4Atovaquone/proguanil + doxycycline for 30 days (1)
Atovaquone/proguanil (1)
Masfrancx et al.16Belgium (2009)1 (75 years), Democratic Rep. CongoFakunleAtovaquone/proguanilCured
Positive OMB
Negative smear
Positive rapid test (Pf HRP-2)
McGregor et al.5United Kingdom (2003–2010)7 but only four confirmed (16–61 years), sub-Saharan Africa (four from Sierra Leone)FakunleDifferent long regimens from 2 months to 3 years4/7 cured three with negative PCR not improved
Positive smear 1/7Chloroquine ± quinine and proguanil
PCR 1/4 (three not done, three negative)Mefloquine + chloroquine and proguanil
Schistosomiasis 3/7 and Hepatitis B 1/7, including two with portal hypertensionAtovaquone/proguanil for 3 years
Bisoffi et al.3Italy (1990–2015)44 (56 years median), from Africa (not specified)FakunleQuinine 3 days + pyrimethamin/sulfametopyrazine one dose, after 2002: ACT but precise regimen not specified20/24 cured or improved others lost to follow-up
Positive smear 22/38
Positive quantitative buffy coat malaria 9/38
Genderini et al. 2018 [current]Belgium (2017)1 (16 years), Guinea ConakryFakunleDihydroartemisinin/piperaquine + doxycycline 6 weeksCured
Positive smear
Positive LAMP

ACT = artemisinin-based combination therapy; HMSS = hyperreactive malarial splenomegaly syndrome; LAMP = loop-mediated isothermal amplification; OMB = osteomedullary biopsy; PCR = polymerase chain reaction; SCD = sickle cell disease.

In conclusion, hyperreactive malarial splenomegaly syndrome is a challenging diagnosis in non-endemic areas. Revised Fakunle’s criteria may guide the diagnosis, and the role of molecular techniques such as LAMP or PCR is emerging to obtain a definite diagnosis in certain cases, a prognosis tool in others. We lack specific treatment guidelines for non-endemic areas: cure may possibly be achieved with an ACT-based short regimen even if this strategy should be validated in larger studies.

REFERENCES

  • 1.

    Bhatia KK, Crane GG, 1989. HLA heterozygosity and hyperreactive malarious splenomegaly in the Upper Watut Valley of Papua New Guinea. P N G Med J 32: 277286.

    • Search Google Scholar
    • Export Citation
  • 2.

    Fakunle YM, Onyewotu II, Greenwood BM, Mohammed I, Holborow EJ, 1978. Cryoglobulinaemia and circulating immune complexes in tropical splenomegaly syndrome. Clin Exp Immunol 31: 5558.

    • Search Google Scholar
    • Export Citation
  • 3.

    Bisoffi Z, Leoni S, Angheben A, Beltrame A, Eseme FE, Gobbi F, Lodesani C, Marocco S, Buonfrate D, 2016. Chronic malaria and hyper-reactive malarial splenomegaly: a retrospective study on the largest series observed in a non-endemic country. Malar J 15: 230.

    • Search Google Scholar
    • Export Citation
  • 4.

    Van den Ende J, van Gompel A, van den Enden E, Taelman H, Vanham G, Vervoort T, 2000. Hyperreactive malaria in expatriates retourning from sub-Saharan Africa. Trop Med Int Health 5: 607611.

    • Search Google Scholar
    • Export Citation
  • 5.

    McGregor A, Doherty T, Lowe P, Chiodini P, Newsholme W, 2015. Hyperreactive malarial splenomegaly syndrome–can the diagnostic criteria be improved? Am J Trop Med Hyg 93: 573576.

    • Search Google Scholar
    • Export Citation
  • 6.

    Mothe B, Lopez-Contreras J, Torres OH, Munoz C, Domingo P, Gurgui M, 2008. A case of hyper-reactive malarial splenomegaly. The role of rapid antigen-detecting and PCR-based tests. Infection 36: 167169.

    • Search Google Scholar
    • Export Citation
  • 7.

    Cheaveau J et al. 2018. Clinical validation of a commercial LAMP test for ruling out malaria in returning travelers: a prospective diagnostic trial. Open Forum Infect Dis 5: ofy260.

    • Search Google Scholar
    • Export Citation
  • 8.

    Ponce C et al. 2017. Diagnostic accuracy of loop-mediated isothermal amplification (LAMP) for screening patients with imported malaria in a non-endemic setting. Parasite 24: 53.

    • Search Google Scholar
    • Export Citation
  • 9.

    Cook J et al. 2015. Loop-mediated isothermal amplification (LAMP) for point-of-care detection of asymptomatic low-density malaria parasite carriers in Zanzibar. Malar J 14: 4348.

    • Search Google Scholar
    • Export Citation
  • 10.

    Puente S, Rubio JM, Subirats M, Lago M, Gonzalez-Lahoz J, Benito A, 2000. The use of PCR in the diagnosis of hyper-reactive malarial splenomegaly (HMS). Ann Trop Med Parasitol 94: 559563.

    • Search Google Scholar
    • Export Citation
  • 11.

    Fakunle YM, 1981. Tropical splenomegaly. Part 1: tropical Africa. Clin Haematol 10: 963975.

  • 12.

    Bates I, Bedu-Addo G, 1997. Review of diagnostic criteria of hyper-reactive malarial splenomegaly. Lancet 349: 1178.

  • 13.

    Fakunle YM, Greenwood BM, 1980. Mortality in tropical splenomegaly syndrome, Trans R Soc Trop Med Hyg 74: 419.

  • 14.

    Leoni S, Buonfrate D, Angheben A, Gobbi F, Bisoffi Z, 2015. The hyper-reactive malarial splenomegaly: a systematic review of the literature. Malar J 14: 185.

    • Search Google Scholar
    • Export Citation
  • 15.

    Camara B, Kantambadouno JB, Martin-Blondel G, Berry A, Alvarez M, Benoit-Vical F, Delmont J, Bouchaud O, Marchou B, 2009. Hyperreactive malarial splenomegaly: three clinical cases and literature review. Med Mal Inf 39: 2935.

    • Search Google Scholar
    • Export Citation
  • 16.

    Masfrancx D, De Munter P, Devos T, 2013. A 75-years -old missionary with fever, splenomegaly and pancytopenia. Acta Clinica Belgica 68: 225228.

    • Search Google Scholar
    • Export Citation
  • 17.

    Aidoo M, Terlouw DJ, Kolczak MS, McElroy PD, ter Kuile FO, Kariuki S, Nahlen BL, Lal AA, Udhayakumar V, 2002. Protective effects of the sickle cell gene against malaria morbidity and mortality. Lancet 359: 13111312.

    • Search Google Scholar
    • Export Citation
  • 18.

    De Franceschi L, Sada S, Andreoli A, Angheben A, Marocco S, Bisoffi Z, 2005. Sickle cell disease and hyperreactive malarial splenomegaly (HMS) in young immigrants from Africa. Blood 106: 44154417.

    • Search Google Scholar
    • Export Citation
  • 19.

    De Iaco G, Saleri N, Perandin F, Gulletta M, Ravizzola G, Manca N, Signorini L, Matteelli A, Prestini K, Castelli F, 2008. Case report: hyper-reactive malarial splenomegaly in a patient with human immunodeficiency virus. Am J Trop Med Hyg 78: 239240.

    • Search Google Scholar
    • Export Citation
  • 20.

    Puente S, Subirats M, Benito A, Rubio JM, Gonzalez-Lahoz JM, 2001. Hyperreactive malarial splenomegaly in Europeans: report of five cases. J Travel Med 8: 322324.

    • Search Google Scholar
    • Export Citation

Author Notes

Address correspondence to Charlotte Martin, Infectious Diseases Department, CHU Saint-Pierre, Brussels, Belgium. E-mail: charlotte_martin@stpierre-bru.be

Authors’ addresses: Francesco G. Genderini, Infectious Diseases Department, Centre Hospitalier Universitaire (CHU) Saint-Pierre, Brussels, Belgium, and Infectious Diseases, Department of Mental and Physical Health and Preventive Medicine, Università della Campania “Luigi Vanvitelli,” Naples, Italy, E-mail: francesco_genderini@stpierre-bru.be. Cecile Haeseleer and Brigitte Cantinieaux, Hematology Department, LHUB-ULB, Centre Hospitalier Universitaire (CHU) Saint-Pierre, Brussels, Belgium, E-mails: cecile.haeseleer@lhub-ulb.be and brigitte.cantinieaux@lhub-ulb.be. Charlotte Martin, Infectious Diseases Department, Centre Hospitalier Universitaire (CHU) Saint-Pierre, Brussels, Belgium, E-mail: charlotte_martin@stpierre-bru.be.

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