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    The patient's peripheral blood smear shows small ring forms as well as appliqué cells, consistent with Plasmodium falciparum.

  • 1.

    Centers for Disease Control and Prevention Treatment Guidelines, 2013. Treatment of Malaria: Guidelines for Clinicians (United States). Available at: http://www.cdc.gov/malaria/resources/pdf/clinicalguidance.pdf. Accessed November 20, 2016.

    • Search Google Scholar
    • Export Citation
  • 2.

    Berrevoets MA, Sprong T, Meis JF, Dofferhoff AS, 2013. Plasmodium falciparum malaria recrudescence occurring 2.5 years after leaving an endemic country. Neth J Med 71: 426428.

    • Search Google Scholar
    • Export Citation
  • 3.

    Arends JE, Oosterheert JJ, Kraaij-Dirkzwager MM, Kaan JA, Fanoy EB, Haas PJ, Scholte EJ, Kortbeek LM, Sankatsing SU, 2013. Two cases of Plasmodium falciparum malaria in The Netherlands without recent travel to a malaria-endemic country. Am J Trop Med Hyg 89: 527530.

    • Search Google Scholar
    • Export Citation
  • 4.

    Szmitko PE, Kohn ML, Simor AE, 2009. Plasmodium falciparum malaria occurring 8 years after leaving an endemic area. Diagn Microbiol Infect Dis 63: 105107.

    • Search Google Scholar
    • Export Citation
  • 5.

    Dierksen J, Al-Ibraheemi A, Wanger A, Chen L, 2016. Plasmodium falciparum recurrence two years after exposure in endemic country: a case report. Ann Clin Lab Sci 46: 433434.

    • Search Google Scholar
    • Export Citation
  • 6.

    Ashley EA, White NJ, 2014. The duration of Plasmodium falciparum infections. Malar J 13: 500.

  • 7.

    Langhorne J, Ndungu FM, Sponaas AM, Marsh K, 2008. Immunity to malaria: more questions than answers. Nat Immunol 9: 725732.

  • 8.

    D'Ortenzio E, Godineau N, Fontanet A, Houze S, Bouchaud O, Matheron S, Le Bras J, 2008. Prolonged Plasmodium falciparum infection in immigrants, Paris. Emerg Infect Dis 14: 323326.

    • Search Google Scholar
    • Export Citation
  • 9.

    Rogerson SJ, Hviid L, Duffy PE, Leke RF, Taylor DW, 2007. Malaria in pregnancy: pathogenesis and immunity. Lancet Infect Dis 7: 105117.

  • 10.

    Ataide R, Mayor A, Rogerson SJ, 2014. Malaria, primigravidae, and antibodies: knowledge gained and future perspectives. Trends Parasitol 30: 8594.

    • Search Google Scholar
    • Export Citation
  • 11.

    O'Neil-Dunne I, Achur RN, Agbor-Enoh ST, Valiyaveettil M, Naik RS, Ockenhouse CF, Zhou A, Megnekou R, Leke R, Taylor DW, Gowda DC, 2001. Gravidity-dependent production of antibodies that inhibit binding of Plasmodium falciparum-infected erythrocytes to placental chondroitin sulfate proteoglycan during pregnancy. Infect Immun 69: 74877492.

    • Search Google Scholar
    • Export Citation
  • 12.

    Alecrim WD, Espinosa FE, Alecrim MG, 2000. Plasmodium falciparum infection in the pregnant patient. Infect Dis Clin North Am 14: 8395, viii–ix.

    • Search Google Scholar
    • Export Citation
  • 13.

    Walters J, 1960. Quiescent malarial parasites. Brit Med J 16: 12061207.

  • 14.

    Mahmood A, 1966. Prolonged latent period with Plasmodium falciparum infections. BMJ 1: 544545.

  • 15.

    Giobbia M, Tonon E, Zanatta A, Cesaris L, Vaglia A, Bisoffi Z, 2005. Late recrudescence of Plasmodium falciparum malaria in a pregnant woman: a case report. Int J Infect Dis 9: 234235.

    • Search Google Scholar
    • Export Citation
  • 16.

    Subramanian D, Moise KJ Jr, White AC Jr, 1992. Imported malaria in pregnancy: report of four cases and review of management. Clin Infect Dis 15: 408413.

    • Search Google Scholar
    • Export Citation
  • 17.

    Jimenez BC, Cuadros-Tito P, Ruiz-Giardin JM, Rojo-Marcos G, Cuadros-Gonzalez J, Canalejo E, Cabello N, San Martin JV, Barrios AM, Hinojosa J, Molina L, 2012. Imported malaria in pregnancy in Madrid. Malar J 11: 112.

    • Search Google Scholar
    • Export Citation
  • 18.

    Kaser AK, Arguin PM, Chiodini PL, Smith V, Delmont J, Jimenez BC, Farnert A, Kimura M, Ramharter M, Grobusch MP, Schlagenhauf P, 2015. Imported malaria in pregnant women: a retrospective pooled analysis. Travel Med Infect Dis 13: 300310.

    • Search Google Scholar
    • Export Citation

 

 

 

 

Recrudescence of Plasmodium falciparum in a Primigravida After Nearly 3 Years of Latency

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  • 1 University of Massachusetts Medical School, Worcester, Massachusetts.
  • 2 Saint Vincent Hospital, Worcester, Massachusetts.

We present a case of a primigravid woman who presented with Plasmodium falciparum nearly 3 years after she last visited a malaria-endemic region. We review the literature to identify case reports of recrudescent P. falciparum malaria during pregnancy, including those with prolonged latency. Reports of recrudescence of P. falciparum during pregnancy are limited. Plasmodium falciparum infection can persist for years. Recrudescence can occur with waning of immunity following departure from endemic areas. Pregnancy, particularly the primigravid state, is a risk factor for severe infection.

Case Report

A 29-year-old primigravid woman presented with fever and thrombocytopenia during her third trimester of pregnancy. Originally from Ghana, she permanently relocated to the United States 5 years ago. She visited Ghana 2¾ years ago for 1 month, but otherwise denies travel outside the United States. She says that she previously had malaria more than 10 times, including during her most recent trip to Ghana for which she did not take chemoprophylaxis and recalls being treated with a several-day course of chloroquine.

At 29 weeks into an otherwise uncomplicated pregnancy, she developed headache, back pain, dark urine, and fever and was admitted to Saint Vincent Hospital in Worcester, MA, for further evaluation. Physical examination revealed a temperature of 101.4°F, blood pressure of 97/57 mmHg, and heart rate of 114 per minute. She was awake, alert, and oriented and her sclerae were anicteric. Heart examination showed tachycardia with no murmurs. Her respiratory examination was normal and her abdomen was soft and protuberant, corresponding with her gestational age, with no tenderness or splenomegaly noted. Results of the back examination and neurological examination were unremarkable. Laboratory evaluation revealed low hemoglobin and platelets of 9.1 g/dL and 36,000/μL, respectively, which were considerably decreased from 11.2 g/dL and 149,000/μL 3 months prior. Other pertinent laboratory values included a total bilirubin of 2.1 mg/dL, direct bilirubin 1.0 mg/dL, and haptoglobin < 15 mg/dL. Her serum glucose, liver enzymes, and creatinine were within normal limits. Both disseminated intravascular coagulation work up and human immunodeficiency virus serology were negative. Thick and thin blood smears revealed 3% parasitemia (∼90,000/μL) with Plasmodium falciparum with small ring forms and appliqué cells (Figure 1). Chest radiograph was normal.

Figure 1.
Figure 1.

The patient's peripheral blood smear shows small ring forms as well as appliqué cells, consistent with Plasmodium falciparum.

Citation: The American Society of Tropical Medicine and Hygiene 96, 3; 10.4269/ajtmh.16-0803

She was given intravenous quinidine (640 mg loading dose followed by 20 mcg/kg/minute), plus intravenous clindamycin 600 mg every 8 hours, then was transferred to the University of Massachusetts Memorial Medical Center in Worcester for more intensive monitoring for high-risk pregnancy. She received betamethasone for fetal lung maturation due to concerns of possible uteroplacental insufficiency in the setting of P. falciparum malaria. Her parasitemia cleared within 72 hours and laboratory abnormalities, including thrombocytopenia, gradually resolved. As she was able to tolerate oral intake by 48 hours, she was switched to oral quinine and clindamycin to complete a 7-day course of antimalarial treatment as an outpatient in accordance with Centers for Disease Control and Prevention (CDC) treatment guidelines.1

The remaining course of her pregnancy was unremarkable. At 38 weeks and 6 days gestation, she had a spontaneous vaginal delivery. Pathology revealed a normal mature placenta and umbilical cord with no signs of malaria burden on microscopic examination. Blood tests that had been collected 5 days after her initial presentation and subsequently processed by the CDC included a P. falciparum indirect fluorescent antibody titer of 1:16,384 (≥ 1:64 is considered elevated) and a polymerase chain reaction (PCR) test that confirmed P. falciparum.

Discussion

Plasmodium falciparum malaria is a major cause of morbidity and mortality worldwide. Although the incubation period is usually between 2 and 4 weeks, asymptomatic P. falciparum infection may persist for many years despite the absence of the hypnozoite stage. Although cases of late occurrence of P. falciparum malaria have been reported between 2 and 9 years after departure from endemic areas,25 the maximum confirmed duration of infection is 13 years.6 Prolonged infection is especially common in highly endemic areas where persistent exposure to malarial antigens may prevent severe disease, but may not completely protect against malaria.7 The appearance of symptoms years after infection may be due to waning of host immunity in semi-immune hosts. A case–control study identified both pregnancy and being an immigrant who never returned to malaria-endemic regions as independent risk factors associated with prolonged P. falciparum infection.8

Pregnant women are at increased risk of malaria infection independent of previously acquired immunity. This is in part due to immune modulation during pregnancy, when a shift toward Th2 responses occurs.9 In addition, P. falciparum–infected erythrocytes can accumulate in the placenta through expression of specific membrane proteins such as VAR2CSA; such variant parasites are unique to pregnancy and render pregnant women highly susceptible to malaria disease and complications.10 Immunoglobulins against VAR2CSA are pregnancy specific and increase with parity, as primigravidae lack antibodies to placental-type parasites but can develop such antibodies during the course of pregnancy if exposed to P. falciparum.11 This provides an explanation for why women pregnant for the first time in a malaria-transmission area are highly susceptible to malaria infection. Pregnant women with malaria infection are particularly prone to developing severe anemia, acute kidney injury, disseminated intravascular coagulation, shock, seizures, and hypoglycemia, whereas obstetric complications include miscarriage, intrauterine death, preterm labor, and low birth weight.12

This case illustrates recrudescence of P. falciparum after a prolonged period of apparent latency during pregnancy. Walters in 1960 and Mahmood in 1966 reported cases of imported P. falciparum in the United Kingdom in Nigerian women after prolonged quiescence, specifically at 17 and 19 months.13,14 In each case, the patient was in the second trimester of pregnancy and presented with anemia. Following diagnosis and treatment, no complications ensued. Giobbia and others described a pregnant patient diagnosed with P. falciparum 4 years after her last stay in an endemic area.15 In their case–control study, D'Ortenzio and others described four pregnant immigrant women who developed clinical malaria more than 3 years after their arrival in Paris, but no additional travel information was provided.7 Of all these cases, only Mahmood described a multigravid patient.14

Limited information has been reported on imported P. falciparum malaria of any duration of recrudescence during pregnancy. In the United States, Subramanian and others described three Nigerian national women each diagnosed with P. falciparum, two during the third trimester and one during the second trimester.16 All had been in Nigeria within 2 months of presentation. Although two had a favorable outcome, one woman who presented with 14% parasitemia expired despite eventual clearance of parasitemia. Jiménez and others in Madrid retrospectively reviewed 19 cases of pregnant women each diagnosed with P. falciparum by microscopy, rapid antigen detection, and/or PCR test for Plasmodium nucleic acid.17 Eighteen patients were multigravid and 53% presented in the third trimester. Nine of 15 symptomatic patients reported symptoms between 7 and 69 days after leaving sub-Saharan endemic areas. About 84% were treated with quinine and clindamycin; no severe complications or deaths were reported, but two had premature abortions. Finally, Käser and others performed a retrospective analysis on 632 pregnant women, who presented with travel-associated malaria in eight non-endemic countries including the United States.18 More than 70% of the cases were P. falciparum malaria. Of all the malaria cases, no maternal deaths were reported, but several fetal abortions occurred; no data were made available on the interval between travel and time of presentation. Of particular note, in all cases, very few women had taken chemoprophylaxis.

Conclusions

Although P. falciparum malaria can be relatively asymptomatic in individuals with high levels of immunity, women such as our patient who reside in non-endemic areas for years have likely lost immunity to malaria and are at increased risk of symptomatic malarial infections after return to endemic areas. Additionally, our patient was at increased risk for malaria given her pregnancy, in particular since she was a primigravida.

Travel to malaria-endemic areas during pregnancy should be avoided or delayed. When unavoidable, chemoprophylaxis should be considered. For pregnant women even with a remote history of travel to malaria-endemic regions, early diagnosis and correct treatment are of paramount importance.

ACKNOWLEDGMENT

We thank Stuart Levitz and Melanie Trombly for helpful comments.

  • 1.

    Centers for Disease Control and Prevention Treatment Guidelines, 2013. Treatment of Malaria: Guidelines for Clinicians (United States). Available at: http://www.cdc.gov/malaria/resources/pdf/clinicalguidance.pdf. Accessed November 20, 2016.

    • Search Google Scholar
    • Export Citation
  • 2.

    Berrevoets MA, Sprong T, Meis JF, Dofferhoff AS, 2013. Plasmodium falciparum malaria recrudescence occurring 2.5 years after leaving an endemic country. Neth J Med 71: 426428.

    • Search Google Scholar
    • Export Citation
  • 3.

    Arends JE, Oosterheert JJ, Kraaij-Dirkzwager MM, Kaan JA, Fanoy EB, Haas PJ, Scholte EJ, Kortbeek LM, Sankatsing SU, 2013. Two cases of Plasmodium falciparum malaria in The Netherlands without recent travel to a malaria-endemic country. Am J Trop Med Hyg 89: 527530.

    • Search Google Scholar
    • Export Citation
  • 4.

    Szmitko PE, Kohn ML, Simor AE, 2009. Plasmodium falciparum malaria occurring 8 years after leaving an endemic area. Diagn Microbiol Infect Dis 63: 105107.

    • Search Google Scholar
    • Export Citation
  • 5.

    Dierksen J, Al-Ibraheemi A, Wanger A, Chen L, 2016. Plasmodium falciparum recurrence two years after exposure in endemic country: a case report. Ann Clin Lab Sci 46: 433434.

    • Search Google Scholar
    • Export Citation
  • 6.

    Ashley EA, White NJ, 2014. The duration of Plasmodium falciparum infections. Malar J 13: 500.

  • 7.

    Langhorne J, Ndungu FM, Sponaas AM, Marsh K, 2008. Immunity to malaria: more questions than answers. Nat Immunol 9: 725732.

  • 8.

    D'Ortenzio E, Godineau N, Fontanet A, Houze S, Bouchaud O, Matheron S, Le Bras J, 2008. Prolonged Plasmodium falciparum infection in immigrants, Paris. Emerg Infect Dis 14: 323326.

    • Search Google Scholar
    • Export Citation
  • 9.

    Rogerson SJ, Hviid L, Duffy PE, Leke RF, Taylor DW, 2007. Malaria in pregnancy: pathogenesis and immunity. Lancet Infect Dis 7: 105117.

  • 10.

    Ataide R, Mayor A, Rogerson SJ, 2014. Malaria, primigravidae, and antibodies: knowledge gained and future perspectives. Trends Parasitol 30: 8594.

    • Search Google Scholar
    • Export Citation
  • 11.

    O'Neil-Dunne I, Achur RN, Agbor-Enoh ST, Valiyaveettil M, Naik RS, Ockenhouse CF, Zhou A, Megnekou R, Leke R, Taylor DW, Gowda DC, 2001. Gravidity-dependent production of antibodies that inhibit binding of Plasmodium falciparum-infected erythrocytes to placental chondroitin sulfate proteoglycan during pregnancy. Infect Immun 69: 74877492.

    • Search Google Scholar
    • Export Citation
  • 12.

    Alecrim WD, Espinosa FE, Alecrim MG, 2000. Plasmodium falciparum infection in the pregnant patient. Infect Dis Clin North Am 14: 8395, viii–ix.

    • Search Google Scholar
    • Export Citation
  • 13.

    Walters J, 1960. Quiescent malarial parasites. Brit Med J 16: 12061207.

  • 14.

    Mahmood A, 1966. Prolonged latent period with Plasmodium falciparum infections. BMJ 1: 544545.

  • 15.

    Giobbia M, Tonon E, Zanatta A, Cesaris L, Vaglia A, Bisoffi Z, 2005. Late recrudescence of Plasmodium falciparum malaria in a pregnant woman: a case report. Int J Infect Dis 9: 234235.

    • Search Google Scholar
    • Export Citation
  • 16.

    Subramanian D, Moise KJ Jr, White AC Jr, 1992. Imported malaria in pregnancy: report of four cases and review of management. Clin Infect Dis 15: 408413.

    • Search Google Scholar
    • Export Citation
  • 17.

    Jimenez BC, Cuadros-Tito P, Ruiz-Giardin JM, Rojo-Marcos G, Cuadros-Gonzalez J, Canalejo E, Cabello N, San Martin JV, Barrios AM, Hinojosa J, Molina L, 2012. Imported malaria in pregnancy in Madrid. Malar J 11: 112.

    • Search Google Scholar
    • Export Citation
  • 18.

    Kaser AK, Arguin PM, Chiodini PL, Smith V, Delmont J, Jimenez BC, Farnert A, Kimura M, Ramharter M, Grobusch MP, Schlagenhauf P, 2015. Imported malaria in pregnant women: a retrospective pooled analysis. Travel Med Infect Dis 13: 300310.

    • Search Google Scholar
    • Export Citation

Author Notes

* Address correspondence to Jennifer P. Wang, University of Massachusetts Medical School, 364 Plantation Street, LRB 219, Worcester, MA 01605-4321. E-mail: jennifer.wang@umassmed.edu

Authors' addresses: Ahmed Al Hammadi and Jennifer P. Wang, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, E-mails: dralhammadi@outlook.com and jennifer.wang@umassmed.edu. Michael Mitchell, Department of Pathology, University of Massachusetts Medical School, Worcester, MA, E-mail: michael.mitchell@umassmemorial.org. George M. Abraham, Saint Vincent Hospital, Worcester, MA, E-mail: george.abraham@stvincenthospital.com.

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