Case of the Wintertime Fever and Chills: A Mosquito Mystery, The
Tavares, Joao
A 20-year-old woman who was 8 months pregnant came to a hospital in Rhode Island in mid-November 2002, because of severe fever and chills. These symptoms had developed seven days earlier prompting her to seek evaluation at an outpatient clinic. A urinary tract infection was diagnosed and she was given oral amoxicillin. Her symptoms did not improve. Five days later she was seen at a different clinic, where treatment was changed to oral nitrofurantoin. Worsening fever and chills prompted her to come to the emergency department.
Born and raised in Gabon, West Africa, the patient came to the US two years previously. She had lived in the New York City area and had come to RI six weeks earlier from Queens, NY. She denied smoking, drinking alcohol, intravenous drug abuse and sexually transmitted disease. She had not received blood transfusions.
Physical examination revealed a young black female who appeared moderately ill. Her temperature was 102.3° F, pulse 120 beats per minute, respirations 20 per minute and blood pressure 90/60 mmHg. Notable findings included scleral icterus; an S4 gallop and a II/VI systolic murmur; mentation was normal. The gravid uterus was nontender and the cervix was closed. The uterine monitor showed 4 contractions per minute and fetal tachycardia with 190-200 beats/min with poor short-term variability. Ultrasound examination estimated gestational age at 34 wks.
Laboratory values included blood glucose 69 mg/dL (70-110 mg/dL) hemoglobin 8.5 g/dL, white blood cell 5,000/ mm^sup 3^, platelets 55,000/mm^sup 3^, total bilirubin 3.0mg/dl and direct bilirubin 1.5, alkaline phosphatase 339 IU/L (50-136IU/ L), LDH 489 IU/L (100-189 IU/L). Urinalysis showed 25-30 white blood cells/HPF, 3+ bacteria and many granular casts. The peripheral blood smear showed intra-erythrocytic ring forms along with extracellular schizonts, consistent with Plasmodium falciparum. (Figures 1 and 2).
The diagnostic and clinical management of this patient posed several important questions: first, how is the diagnosis of malaria established? Second, is malaria more severe in pregnancy? Third, what treatment should be used in pregnancy, and fourth, how did she acquire malaria?
DIAGNOSIS
The diagnosis of malaria is based on clinical features and laboratory findings. The initial symptoms of malaria can be nonspecific such as fever, chills, malaise and headache. The classic malarial paroxysms of fever spikes preceded by chills and rigors followed by profuse diaphoresis result from synchronous waves of parasitemia. While this pattern of fever and chills is very suggestive,1 it is rarely seen even in Plasmodium ovale or Plasmodium vivax malaria.2 Because there are no pathognomonic features of malaria, it is important to ask all individuals with an undifferentiated febrile illness the details of their travel history and whether they have received blood products.
Establishment of the diagnosis of malaria rests on the demonstration of parasites in peripheral blood smears, the detection of malarial antigens, or detection of specific nucleic-acid sequences.3 Stained blood films still remain the gold standard for the diagnosis of malaria.3 A thin smear can be stained and read in less than one hour; and when performed by a well trained microscopist the sensitivity and specificity are excellent. The cost is low, sophisticated laboratory equipment is not needed and, importantly, this technique allows quantitation of parasitemia. Thick smears are useful when thin smears are negative as a greater volume of blood can be examined; however, such smears take several hours to dry and ran be difficult to read for inexperienced persons.
Recently, several new tests that detect malarial antigens have been introduced, but none have performance characteristics that permit them to replace the classical thick and thin smears; histidine-rich protein 2 (HRP-2), plasmodium lactate dehydrogenase (pLDH) and aldolase are a few worth mention. HRP-2 is a water-soluble protein produced by asexual stages and young gametocytes of P. falciparum . It is expressed on the red blood cell (RBC) membrane. pLDH and aldolase are enzymes in the glycolytic pathway of the malaria parasite produced by both sexual and asexual stages. Test methods that detect the malarial antigens mentioned above have reasonably good specificity and sensitivity, although they are not as good as stained blood films. Results can be obtained in twenty minutes and allow only a crude estimation of parasitemia, at a moderate cost. The low skill level required and that the kit is the only equipment needed make them very appealing.
DNA amplification using polymerase chain reaction (PCR) has been developed for all four malaria species which infect humans.3 PCR of whole blood can detect as few as 5 parasites per µl; in comparison a well trained microscopist can detect approximately 50 parasites per µl.3 The disadvantages of PCR are its high cost, technology and skill level requirements. Parasitemia cannot be quantitated and 24 hours are required for results. These attributes make PCR more suitable for developed countries and less feasible for developing areas where trained microscopists are in ready supply.
MALARIA AND PREGNANCY
Although most adults in holoendemic areas are semi-immune to malaria, pregnant women are an exception. Pregnant women, particularly primigravida, develop malaria more frequently and present with a more severe form of malaria than non-pregnant women.4
In P. falciparum infection, adherence of RBCs to endothelium is a key step in pathogenesis. Cytoadhesion is a receptor-mediated process involving a family of immunovariant adhesins, designated Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), expressed on the surface of infected host erythrocytes.4 RBCs with PfEMP1 on the membrane bind to specific receptors on the surface of endothelial cells. In the brain the receptor is CD36 and in the lung, Intercellular adhesion molecule 1 (ICAM-1). Within the placenta and intervillous space the PfEMP1 receptor is chondroitin sulphate A (CSA), which accumulates during normal pregnancy.5 Other receptors that have been identified as targets for P. falciparum adhesins include thrombospondin, vascular cellular adhesion molecule-1, E-selectin, P-selectin and hyaluronic acid.4 Although strains of P. falciparum may bind to more than one tissue receptot, only one strain binds to CSA.4,5
Primigravida and secundigravida have been noted to develop malaria more frequently and more severely than multigravida. At least part of the explanation for this is because large amounts of CSA accumulate in the placenta and intervillous space during pregnancy, providing ample receptors for P. falciparum binding. With subsequent pregnancies anti-adhesion antibodies develop6 and prevent the sequestration of CSA-binding subpopulations of P. falciparum in the placenta. A particularly interesting aspect of this observation is the fact that antibodies against CSA-binding parasites are strain independent which might open the door for a globally applicable vaccine to prevent malaria in pregnancy.6,7,8
Malaria in pregnancy can have considerable complications for the mother including severe anemia, marked hypoglycemia and high level parasitemia.2 Complications for the fetus are low birth weight due to intrauterine growth retardation, premature delivery, stillbirth, and neonatal death.9,10
TREATMENT OF P. FALCIPARUM MALARIA IN PREGNANCY
There are only a limited number of drugs that can be used to treat malaria in pregnancy.11,12,13 In the few areas where chloroquine-sensitive P. falciparum exists, (Central America, north of Panama canal, Haiti and parts of Middle East), chloroquine is the first choice. Resistance to chloroquine is geographically widespread and occurs throughout South America, Africa and southeast Asia. In treatment of malaria acquired in these areas, the medications that can be used safely in pregnancy are quinine alone or combined with clindamycin. Mefloquine is safe but should be avoided in the first trimester. Studies of artemisinin derivatives in pregnancy are ongoing in Asia.11,14
TRANSMISSION OF MALARIA
In nature malaria is transmitted to humans by female anopheline mosquitoes (only the female takes a blood meal; the male anopheline feeds on fruit juice).1 Transmission other than by mosquitoes can be associated with transfusion, syringe sharing and vertical (mother to fetus) transmission. Congenital malaria depends on the extent of placental involvement with malarial parasites.14
OUR PATIENT
The diagnosis of malaria was established by examination by light microscopy of Giemsa-stained thin smears; confirmation of sole P. falciparum infection was by PCR at the Centers for Disease Control. The initial parasitemia of 2.5% fell to less than 0.5% over 2 days with treatment with quinine and clindamycin. (Figure 3)
The patient denied travel to a P. falciparum endemic area in the preceding 2 years as well as blood transfusion or IVDU. Although she had emigrated 2 yrs earlier from Gabon, an area endemic for malaria, the species of malaria causing her infection, P. falciparum, is not a late relapsing type of malaria. Alternate possibilities for acquiring infection were considered. During the summer months preceding this illness, she had lived in Queens, New York, less than 12 km from JFK International Airport. Her apartment did not have window screens and she recalled being bitten by mosquitoes. Local transmission of malaria to persons living near airports has occurred by infected mosquitos transported on aircraft arriving from endemic areas for malaria.15,16 It was also possible that she had unacknowledged travel to an area endemic for P. falciparum.
In addition to anti-malarials, the patient was treated with vigorous supportive care which included acetaminophen to control fever, vigorous fluid resuscitation, RBC transfusion and oxygen. Uterine contractions slowed and then stopped within 24 hrs and the patient was afebrile by the third hospital day. Several episodes of hypoglycemia occurred, which were probably multifactorial in etiology, being due to late pregnancy, malaria itself and quinine. She completed a 7-day course of quinine and clindamycin and was discharged. Six weeks later she delivered a healthy term infant boy weighing 6 lbs, 13 oz. The mother was not parasitemic at birth and the baby was not treated. Placental pathology showed tiny infarctions involving less than 1% of placenta without evidence of malaria.
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Joao Tavares, MD, Raymond Lewis, MD, Darius Kostrzewa, MD, Stanley Schwatz, MD, and Marguerite A. Neill, MD
Joao Tavares, MD, is a second year fellow in Infectious Diseases.
Ramond Lewis, MD, is a fellow in Maternal Child Health.
Darius Kostrzewa, MD, is a resident in Family Medicine.
Stanley Schwanz, MD, is a Clinical Assistant Professor of Pathology and Laboratory Medicine.
Marguerite Neill, MD, is an Associate Professor of Medicine in the Division of Infectious Disease.
All authors are in the Brown Medical School.
CORRESPONDENCE:
Marguerite A. Neill, MD
Memorial Hospital of Rhode Island
111 Brewster Street
Pawtucket, RI 02860
Phone: (401) 729-2534
E-mail: Marguerite_Neill@brown.edu
Copyright Rhode Island Medical Society Nov 2003
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