Leukoerythroblastosis in a Young Child with Severe Malaria and Superimposed Gram Negative Infection

Leukoerythroblastosis in a Young Child with Severe Malaria and Superimposed Gram Negative Infection Abstract Background Leukoerythroblastosis, a non-specific and often short-lasting response of the bone marrow to different diseases such as malignancies or infections, is characterized by the presence in the peripheral blood of immature red and white cells. Methods We present a case of leukoerythoblastosis occurring in a 24 months old Mozambican girl, in the context of a severe malaria episode and an associated urinary tract infection. Peripheral blood smear was used for diagnosis of malaria and leukoerythroblastosis. Enterobacter cloacae isolation and antibiotic susceptibility testing were performed by conventional microbiology. Results Peripheral blood smear was positive for Plasmodium falciparum and showed a leukoerythroblastosis with red cell anisopoikilocytosis and left shifted neutrophils. Urine culture confirmed the presence of a multi-resistant E. cloacae. Treatment of underlying conditions resolved the leukoerythroblastic reaction. Conclusions Leukoerythroblastosis may be related to different infectious diseases and may also appear in the context of severe malaria. Bacterial superinfection needs to be investigated. leukoerythroblastosis, malaria, gram negative infection, urinary tract infection INTRODUCTION Malaria patients can present with different haematological alterations affecting all cell lines. White blood cell count (WBCC) is often affected, and changes in every white blood cell line have been described. If WBCC left shift is accompanied by red blood cells (RBCs), leukoerythroblastosis should be contemplated. Leukoerythroblastosis is defined as the presence of immature cells of the myeloid series and nucleated red blood cells (nRBCs) in the circulating blood, with or without anaemia [1]. Leukoerythroblastosis can be associated with different pathologies, including infectious diseases [2]. Leukoerythroblastic reactions have been mainly found to affect adults [3] and only a few cases have been reported in children [4–7]. Some of those cases were attributed to infections. We present a leukoerythroblastic reaction in a Mozambican child, occurring in the context of a severe malaria episode with an associated bacterial sepsis from urinary origin. CASE REPORT The patient, a 24 months old Mozambican girl, was admitted with a 3 day history of fever and general malaise after starting treatment for uncomplicated malaria on a local facility 2 days before admission. On the day of admission, she developed four episodes of generalized tonic-clonic seizures, and was transferred to Manhiça District Hospital with suspicion of severe malaria. The patient had no relevant past clinical history. On examination, the child was fully conscious but in a general poor condition, presenting fever, tachypnoea, tachycardia, prostration and pallor. There were no other relevant findings on examination. Peripheral blood smear was positive for Plasmodium falciparum with a parasitaemia of 47 065 parasites/μl. Human immunodeficiency virus test on admission was negative. Initial laboratory tests showed a haemoglobin of 5.5 g/dl, RBCs of 2.03 × 103/μl, haematocrit of 16.6% and a WBCC of 33.73 × 103 leukocytes/μl with a differential count of neutrophils 37.4%, lymphocytes 54%, monocytes 8.3%, eosinophils 0.1% and basophils 0.1%. No others important laboratory results were reported. Treatment including parenteral artesunate, empirical ceftriaxone and blood transfusion was initiated. The patient showed a good clinical evolution, and fever disappeared after 32 h. Parasite clearance was demonstrated at 42 h. After three doses of artesunate, a complementary full course of oral artemether-lumefantrine was administered, according to Mozambican National guidelines for treatment of malaria. Forty-eight hours after admission, the patient’s clinical status worsened, developing fever again and showing an escalating WBCC peaking at 138.5 × 103 leukocytes/μl at Day 5 after admission. A peripheral blood smear obtained on Day 6 confirmed an elevated WBCC (manually calculated at around 28 × 103 leukocytes/μl), although of a much lesser magnitude than the 78.13 × 103 leukocytes/μl reported at the same time by the automated coulter haemogram counter. The haematopathologist report described a leukoerythroblastosis with red cell anisopoikilocytosis and left shifted neutrophils (Figure 1). Although bone narrow examination is essential for making a definitive diagnosis, no bone marrow sample could be obtained because of lack of site resources. Malignancies and erythrocyte abnormalities were ruled out considering the information provided by the blood smear and the clinical evolution. New samples of blood and urine were taken for cultures, and antibiotic was switched empirically from ceftriaxone to ciprofloxacin with temperature normalization 24 h later. Subsequently, the urine culture obtained on Day 6 grew a multi-resistant Enterobacter cloacae resistant to ceftriaxone and sensible to ciprofloxacin. No microorganism was isolated in the first and second blood cultures. The patient also presented a drop of haemoglobin at 98 and 174  h to 4.8 and 4.3 g/dl, respectively, requiring two additional blood transfusions. After those interventions, the patient improved swiftly, with temperature and WBCC normalization, and was discharged on Day 10 with a haemoglobin of 7.9 g/dl and WBCC of 17.27 × 103/μl. On Day 14 after admission, an outpatient clinical and laboratory control was made. The patient remained asymptomatic and her haemogram showed a haemoglobin of 7.7 g/dl, RBCs of 2.03 × 103/μl, haematocrit of 26% and WBCC of 12.17 × 103 leukocytes/μl with a normal WBCC. Fig. 1. View largeDownload slide Peripheral blood smear (May-Grunwald Giemsa staining) showing a leukoerythroblastic reaction, with some neutrophils, one metamyelocyte and two erythroblasts, together with marked anisopoikilocytosis of the erythrocytes. Fig. 1. View largeDownload slide Peripheral blood smear (May-Grunwald Giemsa staining) showing a leukoerythroblastic reaction, with some neutrophils, one metamyelocyte and two erythroblasts, together with marked anisopoikilocytosis of the erythrocytes. DISCUSSION Different leukocyte alteration patterns have been reported in relation to malaria infections, including normal WBCC, leukopenia and leukocytosis [8–13]. Differential diagnosis of WBCC alterations is challenging, particularly in poor settings where diagnostic resources and specialized staff are scarce. Those alterations are normally detected by automated haematology analysers, and in certain circumstances, it is recommended to obtain a peripheral blood smear, and whenever possible, conduct a bone marrow examination [14]. The microscopic observation of the peripheral blood smear may not only quantify the real magnitude of the WBBC elevation but can also detect qualitative abnormalities in all haematological series, including leukocytes, erythrocytes and platelets [14]. If WBCC left shift is accompanied by RBCs, leukoerythroblastosis should be considered. Leukoerythroblastosis is characterized by the appearance of immature cells of the myeloid series and nRBCs in the circulating blood, with or without anaemia [1]. Leukoerythroblastosis has been better defined in adults [3] and can appear as a result of a wide range of diseases including leukaemia or malignancies, infections, haemorrhages or drug reactions [14, 15]. In children, only a handful of cases have been reported, associated with malignancy [4], parvovirus B19 infections [5, 6] or inguinal abscess [7]. When the underlying condition is treated, WBCC normalizes rapidly, leading to the resolution of the leukoerythroblastic reaction, as occurred in this case. Although the relative weight of malaria infection and its relationship with leukoerythroblastosis cannot be ruled out, the timeline of events suggests that in this case it was mainly caused by a bacterial sepsis of urinary origin. The coexistence of malaria and superimposed bacterial infections is relatively frequent and entails a poorer prognosis [16]. This case report is illustrative of such an association, with the initial severe P. falciparum infection being complicated by a urinary tract infection because of a multi-resistant E.cloacae, with the previously unreported particularity of being expressed as a leukoerythoblastosis. CONCLUSIONS Leukoerythroblastosis in childhood may be related to different diseases including infections of a transient and acute nature. Differential diagnosis is challenging in poor settings with lack of laboratory facilities and specialized staff. In the context of a severe malaria episode, it may reflect a coexisting infection that needs to be further investigated. Acknowledgements We are indebted to the family of the child described in this article. We are grateful for the work conducted by the staff at both the Manhiç¸a District Hospital. We are also grateful for the laboratory work conducted at CISM. Funding No specific funding was required for this study. The Spanish Agency of cooperation and International development (AECID) funds the core activities of Centro de Investigação em Saúde de Manhiça (CISM). Rosauro Varo has a fellowship (CD16/00024) from the program Rio Hortega of the Instituto de Salud “Carlos III” (ISCIII). References 1 Wintrobe MM. Wintrobe's Clinical Hematology. Lippincott Williams & Wilkins, Philadelphia , 2009 . 2 Brigden ML , Page N. Leukoerythroblastosis: a much maligned phenomenon? CMAJ 1987 ; 137 : 785 – 6 . Google Scholar PubMed 3 Burkett LL , Cox ML , Fields ML. Leukoerythroblastosis in the adult . Am J Clin Pathol 1965 ; 44 : 494 – 8 . http://dx.doi.org/10.1093/ajcp/44.5.494 Google Scholar CrossRef Search ADS PubMed 4 Couselo Sánchez JM , Méndez Rodriguez I , Fuster Siebert M , et al. [Leukoerythroblastosis as a manifestation of disseminated neuroblastoma in childhood] . Rev Esp Oncol 1980 ; 27 : 571 – 8 . Google Scholar PubMed 5 Gulen H , Basarir F , Hakan N , et al. Premature labor and leukoerythroblastosis in a newborn with parvovirus B19 infection . Haematologica 2005 ; 90(Suppl) : ECR38 . Google Scholar PubMed 6 Duran R , Vatansever U , Acunas B , et al. Transient leukoerythroblastosis in a very low birth weight infant with parvovirus B19 infection . Int J Infect Dis 2009 ; 13 : e473 – 5 . Google Scholar CrossRef Search ADS PubMed 7 Canbolat Ayhan A , Timur C , Ayhan Y , Kes G. Leukoerythroblastosis Mimicking Leukemia: a case report . Iran J Pediatr 2014 ; 24 : 332 – 3 . Google Scholar PubMed 8 Tobon-Castano A , Mesa-Echeverry E , Miranda-Arboleda AF. Leukogram profile and clinical status in vivax and falciparum malaria patients from Colombia . J Trop Med 2015 ; 2015 : 796182 . Google Scholar CrossRef Search ADS PubMed 9 Taylor WR , Widjaja H , Basri H , et al. Changes in the total leukocyte and platelet counts in Papuan and non Papuan adults from northeast Papua infected with acute Plasmodium vivax or uncomplicated Plasmodium falciparum malaria . Malar J 2008 ; 7 : 259 . http://dx.doi.org/10.1186/1475-2875-7-259 Google Scholar CrossRef Search ADS PubMed 10 Wickramasinghe SN , Abdalla SH. Blood and bone marrow changes in malaria . Baillieres Best Pract Res Clin Haematol 2000 ; 13 : 277 – 99 . http://dx.doi.org/10.1053/beha.1999.0072 Google Scholar CrossRef Search ADS PubMed 11 Ladhani S , Lowe B , Cole AO , et al. Changes in white blood cells and platelets in children with falciparum malaria: relationship to disease outcome . Br J Haematol 2002 ; 119 : 839 – 47 . http://dx.doi.org/10.1046/j.1365-2141.2002.03904.x Google Scholar CrossRef Search ADS PubMed 12 Orago AS , Wattimah DN , Aloka PL , et al. An analysis of haematological parameters in patients and individual residents of a Plasmodium falciparum malaria holoendemic area of western Kenya . Microbios 2001 ; 106(Suppl 2) : 117 – 32 . Google Scholar PubMed 13 Sowunmi A , Akindele JA , Balogun MA. Leukocyte counts in falciparum malaria in African children from an endemic area . Afr J Med Med Sci 1995 ; 24 : 145 – 9 . Google Scholar PubMed 14 George TI. Malignant or benign leukocytosis . Hematology Am Soc Hematol Educ Program 2012 ; 2012 : 475 – 84 . Google Scholar PubMed 15 Halkes CJ , Dijstelbloem HM , Eelkman Rooda SJ , Kramer MH. Extreme leucocytosis: not always leukaemia . Neth J Med 2007 ; 65 : 248 – 51 . Google Scholar PubMed 16 Bassat Q , Guinovart C , Sigauque B , et al. Severe malaria and concomitant bacteraemia in children admitted to a rural Mozambican hospital . Trop Med Int Health 2009 ; 14 : 1011 – 19 . http://dx.doi.org/10.1111/j.1365-3156.2009.02326.x Google Scholar CrossRef Search ADS PubMed © The Author(s) [2017]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Tropical Pediatrics Oxford University Press

Leukoerythroblastosis in a Young Child with Severe Malaria and Superimposed Gram Negative Infection

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Abstract

Abstract Background Leukoerythroblastosis, a non-specific and often short-lasting response of the bone marrow to different diseases such as malignancies or infections, is characterized by the presence in the peripheral blood of immature red and white cells. Methods We present a case of leukoerythoblastosis occurring in a 24 months old Mozambican girl, in the context of a severe malaria episode and an associated urinary tract infection. Peripheral blood smear was used for diagnosis of malaria and leukoerythroblastosis. Enterobacter cloacae isolation and antibiotic susceptibility testing were performed by conventional microbiology. Results Peripheral blood smear was positive for Plasmodium falciparum and showed a leukoerythroblastosis with red cell anisopoikilocytosis and left shifted neutrophils. Urine culture confirmed the presence of a multi-resistant E. cloacae. Treatment of underlying conditions resolved the leukoerythroblastic reaction. Conclusions Leukoerythroblastosis may be related to different infectious diseases and may also appear in the context of severe malaria. Bacterial superinfection needs to be investigated. leukoerythroblastosis, malaria, gram negative infection, urinary tract infection INTRODUCTION Malaria patients can present with different haematological alterations affecting all cell lines. White blood cell count (WBCC) is often affected, and changes in every white blood cell line have been described. If WBCC left shift is accompanied by red blood cells (RBCs), leukoerythroblastosis should be contemplated. Leukoerythroblastosis is defined as the presence of immature cells of the myeloid series and nucleated red blood cells (nRBCs) in the circulating blood, with or without anaemia [1]. Leukoerythroblastosis can be associated with different pathologies, including infectious diseases [2]. Leukoerythroblastic reactions have been mainly found to affect adults [3] and only a few cases have been reported in children [4–7]. Some of those cases were attributed to infections. We present a leukoerythroblastic reaction in a Mozambican child, occurring in the context of a severe malaria episode with an associated bacterial sepsis from urinary origin. CASE REPORT The patient, a 24 months old Mozambican girl, was admitted with a 3 day history of fever and general malaise after starting treatment for uncomplicated malaria on a local facility 2 days before admission. On the day of admission, she developed four episodes of generalized tonic-clonic seizures, and was transferred to Manhiça District Hospital with suspicion of severe malaria. The patient had no relevant past clinical history. On examination, the child was fully conscious but in a general poor condition, presenting fever, tachypnoea, tachycardia, prostration and pallor. There were no other relevant findings on examination. Peripheral blood smear was positive for Plasmodium falciparum with a parasitaemia of 47 065 parasites/μl. Human immunodeficiency virus test on admission was negative. Initial laboratory tests showed a haemoglobin of 5.5 g/dl, RBCs of 2.03 × 103/μl, haematocrit of 16.6% and a WBCC of 33.73 × 103 leukocytes/μl with a differential count of neutrophils 37.4%, lymphocytes 54%, monocytes 8.3%, eosinophils 0.1% and basophils 0.1%. No others important laboratory results were reported. Treatment including parenteral artesunate, empirical ceftriaxone and blood transfusion was initiated. The patient showed a good clinical evolution, and fever disappeared after 32 h. Parasite clearance was demonstrated at 42 h. After three doses of artesunate, a complementary full course of oral artemether-lumefantrine was administered, according to Mozambican National guidelines for treatment of malaria. Forty-eight hours after admission, the patient’s clinical status worsened, developing fever again and showing an escalating WBCC peaking at 138.5 × 103 leukocytes/μl at Day 5 after admission. A peripheral blood smear obtained on Day 6 confirmed an elevated WBCC (manually calculated at around 28 × 103 leukocytes/μl), although of a much lesser magnitude than the 78.13 × 103 leukocytes/μl reported at the same time by the automated coulter haemogram counter. The haematopathologist report described a leukoerythroblastosis with red cell anisopoikilocytosis and left shifted neutrophils (Figure 1). Although bone narrow examination is essential for making a definitive diagnosis, no bone marrow sample could be obtained because of lack of site resources. Malignancies and erythrocyte abnormalities were ruled out considering the information provided by the blood smear and the clinical evolution. New samples of blood and urine were taken for cultures, and antibiotic was switched empirically from ceftriaxone to ciprofloxacin with temperature normalization 24 h later. Subsequently, the urine culture obtained on Day 6 grew a multi-resistant Enterobacter cloacae resistant to ceftriaxone and sensible to ciprofloxacin. No microorganism was isolated in the first and second blood cultures. The patient also presented a drop of haemoglobin at 98 and 174  h to 4.8 and 4.3 g/dl, respectively, requiring two additional blood transfusions. After those interventions, the patient improved swiftly, with temperature and WBCC normalization, and was discharged on Day 10 with a haemoglobin of 7.9 g/dl and WBCC of 17.27 × 103/μl. On Day 14 after admission, an outpatient clinical and laboratory control was made. The patient remained asymptomatic and her haemogram showed a haemoglobin of 7.7 g/dl, RBCs of 2.03 × 103/μl, haematocrit of 26% and WBCC of 12.17 × 103 leukocytes/μl with a normal WBCC. Fig. 1. View largeDownload slide Peripheral blood smear (May-Grunwald Giemsa staining) showing a leukoerythroblastic reaction, with some neutrophils, one metamyelocyte and two erythroblasts, together with marked anisopoikilocytosis of the erythrocytes. Fig. 1. View largeDownload slide Peripheral blood smear (May-Grunwald Giemsa staining) showing a leukoerythroblastic reaction, with some neutrophils, one metamyelocyte and two erythroblasts, together with marked anisopoikilocytosis of the erythrocytes. DISCUSSION Different leukocyte alteration patterns have been reported in relation to malaria infections, including normal WBCC, leukopenia and leukocytosis [8–13]. Differential diagnosis of WBCC alterations is challenging, particularly in poor settings where diagnostic resources and specialized staff are scarce. Those alterations are normally detected by automated haematology analysers, and in certain circumstances, it is recommended to obtain a peripheral blood smear, and whenever possible, conduct a bone marrow examination [14]. The microscopic observation of the peripheral blood smear may not only quantify the real magnitude of the WBBC elevation but can also detect qualitative abnormalities in all haematological series, including leukocytes, erythrocytes and platelets [14]. If WBCC left shift is accompanied by RBCs, leukoerythroblastosis should be considered. Leukoerythroblastosis is characterized by the appearance of immature cells of the myeloid series and nRBCs in the circulating blood, with or without anaemia [1]. Leukoerythroblastosis has been better defined in adults [3] and can appear as a result of a wide range of diseases including leukaemia or malignancies, infections, haemorrhages or drug reactions [14, 15]. In children, only a handful of cases have been reported, associated with malignancy [4], parvovirus B19 infections [5, 6] or inguinal abscess [7]. When the underlying condition is treated, WBCC normalizes rapidly, leading to the resolution of the leukoerythroblastic reaction, as occurred in this case. Although the relative weight of malaria infection and its relationship with leukoerythroblastosis cannot be ruled out, the timeline of events suggests that in this case it was mainly caused by a bacterial sepsis of urinary origin. The coexistence of malaria and superimposed bacterial infections is relatively frequent and entails a poorer prognosis [16]. This case report is illustrative of such an association, with the initial severe P. falciparum infection being complicated by a urinary tract infection because of a multi-resistant E.cloacae, with the previously unreported particularity of being expressed as a leukoerythoblastosis. CONCLUSIONS Leukoerythroblastosis in childhood may be related to different diseases including infections of a transient and acute nature. Differential diagnosis is challenging in poor settings with lack of laboratory facilities and specialized staff. In the context of a severe malaria episode, it may reflect a coexisting infection that needs to be further investigated. Acknowledgements We are indebted to the family of the child described in this article. We are grateful for the work conducted by the staff at both the Manhiç¸a District Hospital. We are also grateful for the laboratory work conducted at CISM. Funding No specific funding was required for this study. The Spanish Agency of cooperation and International development (AECID) funds the core activities of Centro de Investigação em Saúde de Manhiça (CISM). Rosauro Varo has a fellowship (CD16/00024) from the program Rio Hortega of the Instituto de Salud “Carlos III” (ISCIII). References 1 Wintrobe MM. Wintrobe's Clinical Hematology. Lippincott Williams & Wilkins, Philadelphia , 2009 . 2 Brigden ML , Page N. Leukoerythroblastosis: a much maligned phenomenon? CMAJ 1987 ; 137 : 785 – 6 . Google Scholar PubMed 3 Burkett LL , Cox ML , Fields ML. Leukoerythroblastosis in the adult . Am J Clin Pathol 1965 ; 44 : 494 – 8 . http://dx.doi.org/10.1093/ajcp/44.5.494 Google Scholar CrossRef Search ADS PubMed 4 Couselo Sánchez JM , Méndez Rodriguez I , Fuster Siebert M , et al. [Leukoerythroblastosis as a manifestation of disseminated neuroblastoma in childhood] . Rev Esp Oncol 1980 ; 27 : 571 – 8 . Google Scholar PubMed 5 Gulen H , Basarir F , Hakan N , et al. Premature labor and leukoerythroblastosis in a newborn with parvovirus B19 infection . Haematologica 2005 ; 90(Suppl) : ECR38 . Google Scholar PubMed 6 Duran R , Vatansever U , Acunas B , et al. Transient leukoerythroblastosis in a very low birth weight infant with parvovirus B19 infection . Int J Infect Dis 2009 ; 13 : e473 – 5 . Google Scholar CrossRef Search ADS PubMed 7 Canbolat Ayhan A , Timur C , Ayhan Y , Kes G. Leukoerythroblastosis Mimicking Leukemia: a case report . Iran J Pediatr 2014 ; 24 : 332 – 3 . Google Scholar PubMed 8 Tobon-Castano A , Mesa-Echeverry E , Miranda-Arboleda AF. Leukogram profile and clinical status in vivax and falciparum malaria patients from Colombia . J Trop Med 2015 ; 2015 : 796182 . Google Scholar CrossRef Search ADS PubMed 9 Taylor WR , Widjaja H , Basri H , et al. Changes in the total leukocyte and platelet counts in Papuan and non Papuan adults from northeast Papua infected with acute Plasmodium vivax or uncomplicated Plasmodium falciparum malaria . Malar J 2008 ; 7 : 259 . http://dx.doi.org/10.1186/1475-2875-7-259 Google Scholar CrossRef Search ADS PubMed 10 Wickramasinghe SN , Abdalla SH. Blood and bone marrow changes in malaria . Baillieres Best Pract Res Clin Haematol 2000 ; 13 : 277 – 99 . http://dx.doi.org/10.1053/beha.1999.0072 Google Scholar CrossRef Search ADS PubMed 11 Ladhani S , Lowe B , Cole AO , et al. Changes in white blood cells and platelets in children with falciparum malaria: relationship to disease outcome . Br J Haematol 2002 ; 119 : 839 – 47 . http://dx.doi.org/10.1046/j.1365-2141.2002.03904.x Google Scholar CrossRef Search ADS PubMed 12 Orago AS , Wattimah DN , Aloka PL , et al. An analysis of haematological parameters in patients and individual residents of a Plasmodium falciparum malaria holoendemic area of western Kenya . Microbios 2001 ; 106(Suppl 2) : 117 – 32 . Google Scholar PubMed 13 Sowunmi A , Akindele JA , Balogun MA. Leukocyte counts in falciparum malaria in African children from an endemic area . Afr J Med Med Sci 1995 ; 24 : 145 – 9 . Google Scholar PubMed 14 George TI. Malignant or benign leukocytosis . Hematology Am Soc Hematol Educ Program 2012 ; 2012 : 475 – 84 . Google Scholar PubMed 15 Halkes CJ , Dijstelbloem HM , Eelkman Rooda SJ , Kramer MH. Extreme leucocytosis: not always leukaemia . Neth J Med 2007 ; 65 : 248 – 51 . Google Scholar PubMed 16 Bassat Q , Guinovart C , Sigauque B , et al. Severe malaria and concomitant bacteraemia in children admitted to a rural Mozambican hospital . Trop Med Int Health 2009 ; 14 : 1011 – 19 . http://dx.doi.org/10.1111/j.1365-3156.2009.02326.x Google Scholar CrossRef Search ADS PubMed © The Author(s) [2017]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

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Journal of Tropical PediatricsOxford University Press

Published: Dec 18, 2017

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