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Background
This world-wide parasitic infection still torments us.
OUTLINE
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS INCIDENCE/
PREVALENCEAGE SEX GEOGRAPHY EPIDEMIOLOGIC ASSOCIATIONS
DISEASE ASSOCIATIONS CHARACTERIZATION HIV-AIDS
- HIV increases the risk of malaria in women of all gravidities in Kisumu, Kenya.
van Eijk AM, Ayisi JG, ter Kuile FO, Misore AO, Otieno JA, Rosen DH, Kager PA, Steketee RW, Nahlen BL.
Kenya Medical Research Institute, Center for Vector Biology and Control Research, Kisumu, Kenya.
AIDS. 2003 Mar 7;17(4):595-603. Abstract quote
OBJECTIVE: To study the importance of HIV infection for malaria in pregnancy in Kisumu, Kenya.
SUBJECTS AND METHODS: Healthy women with an uncomplicated pregnancy of 32 weeks or more attending the prenatal clinic in the Provincial Hospital between June 1996 and March 1999 were tested for HIV and malaria after consent had been obtained. For participating women who delivered in the same hospital, a blood smear of the mother and the placenta were obtained.
RESULTS: In the third trimester, 5093 women consented to testing: the prevalence of malaria and HIV was 20.1 and 24.9%, respectively. Among the 2502 screened women who delivered in the hospital, the prevalence of HIV, peripheral parasitaemia and placental malaria was 24.5, 15.2, and 19.0%, respectively. Compared with HIV-seronegative women, HIV-seropositive women were more likely to be parasitaemic, to have higher parasite densities, and to be febrile when parasitaemic. Placental infections in HIV-seropositive women were more likely to be chronic, as indicated by the presence of moderate to heavy pigment depositions. When adjusted by age, the typical gravidity-specific pattern of malaria in pregnancy disappeared in HIV-seropositive women; HIV-seropositive primigravidae had a similar risk of malaria as HIV-seropositive multigravidae. The excess malaria attributable to HIV in the third trimester increased from 34.6% among HIV-seropositive primigravidae, to 41.5% among HIV-seropositive secundigravidae, and 50.7% among HIV-seropositive gravidae with three or more pregnancies.
CONCLUSION: HIV infection alters patterns of malaria in pregnant women; in areas with both infections, all pregnant women should use malaria prevention.
PATHOGENESIS CHARACTERIZATION APOPTOSIS
Curr Top Microbiol Immunol. 2005;289:185-217. Abstract quote
Malaria parasites of the genus Plasmodium are transmitted from host to host by mosquitoes. Sexual reproduction occurs in the blood meal and the resultant motile zygote, the ookinete, migrates through the midgut epithelium and transforms to an oocyst under the basal lamina. After sporogony, sporozoites are released into the mosquito haemocoel and invade the salivary gland before injection when next the mosquito feeds on a host. Interactions between parasite and vector occur at all stages of the establishment and development of the parasite and some of these result in the death of parasite and host cells by apoptosis.
Infection-induced programmed cell death occurs in patches of follicular epithelial cells in the ovary, resulting in follicle resorption and thus a reduction in egg production.
We argue that fecundity reduction will result in a change in resource partitioning that may benefit the parasite. Apoptosis also occurs in cells of the midgut epithelium that have been invaded by the parasite and are subsequently expelled into the midgut. In addition, the parasite itself dies by a process of programmed cell death (PCD) in the lumen of the midgut before invasion has occurred.
Caspase-like activity has been detected in the cytoplasm of the ookinetes, despite the absence of genes homologous to caspases in the genome of this, or any, unicellular eukaryote. The putative involvement of other cysteine proteases in ancient apoptotic pathways is discussed. Potential signal pathways for induction of apoptosis in the host and parasite are reviewed and we consider the evidence that nitric oxide may play a role in this induction.
Finally, we consider the hypothesis that death of some parasites in the midgut will limit infection and thus prevent vector death before the parasites have developed into mature sporozoites.
LABORATORY/
RADIOLOGIC/
OTHER TESTSCHARACTERIZATION RADIOLOGIC MRI
J Neuroimaging. 2005 Jul;15(3):278-80. Abstract quote
Cerebral malaria occurs in 2% of patients infected by Plasmodium falciparum. Magnetic resonance imaging findings of small white matter infarcts due to cerebral malaria have been previously reported, however nonspecific.
Since diffusion-weighted imaging can differentiate acute embolic infarcts from other chronic or nonspecific white matter lesions, it may aid diagnosis of this illness in patients who travel to endemic areas.LABORATORY MARKERS PCR
- Real-time quantitative PCR for determining the burden of Plasmodium falciparum parasites during pregnancy and infancy.
Malhotra I, Dent A, Mungai P, Muchiri E, King CL.
Center for Global Health and Diseases, Case Western Reserve University, 2103 Cornell Rd., WRC Rm. 4132, Cleveland, OH 44106-7286, USA.
J Clin Microbiol. 2005 Aug;43(8):3630-5. Abstract quote
Real-time quantitative PCR (RTQ-PCR) provides a quick, accurate, and reproducible quantification of parasites. However, the value of RTQ-PCR for predicting clinical outcomes of malaria is unknown.
Here, we compared RTQ-PCR to microscopy of blood smears, nested PCR (nPCR), and parasite circulating-antigen (CAg) assays for detection of Plasmodium falciparum in pregnant Kenyan women and their infants and related these findings to parity and birth weights in their newborns (n = 554). nPCR was the most sensitive assay for detection of malaria in pregnancy, followed in decreasing order of sensitivity by RTQ-PCR, CAg assays, and blood smears. RTQ-PCR detected a higher frequency of malaria infection (46%) in maternal peripheral blood in primiparous than in multiparous women (35%; P < 0.001), with a >12-fold difference in parasite burden (geometric mean = 25,870 versus 2,143 amplicons/microl blood; P < 0.0001). Similarly, the presence of placental malaria determined by RTQ-PCR was approximately twofold higher in primiparous versus multiparous women (21% versus 13%; P < 0.01).
The presence and intensity of malaria infection in pregnant women estimated by RTQ-PCR strongly correlated with low-birth-weight babies, especially in those with high amplicon numbers. RTQ-PCR identified malaria-infected women, missed by blood smear, who were at risk for having underweight offspring. By contrast, malaria detected by nPCR and CAg assay showed a much weaker association with parity or low birth weight.
Thus, RTQ-PCR provides an estimate of parasite burden that is more sensitive than blood smear and is predictive of clinical outcomes of malaria infection in pregnant women and newborns.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION GENERAL VARIANTS
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL
SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHERCHARACTERIZATION SPECIAL STAINS IMMUNOPEROXIDASE ELECTRON MICROSCOPY IMMUNOFLUORESCENCE
Sameer S. Talwalkar, MD, etal.
The key to reducing mortality and morbidity associated with malaria is rapid diagnosis and early, effective therapy. Berberine, a plant alkaloid, has been used for fluorescent staining of the Y chromosome.
We evaluated whether berberine can be used for staining of malarial parasites in 40 selected peripheral blood smears from patients with clinical symptoms of malaria; smears were evaluated with OptiMal (DiaMed, Miami, FL) and Giemsa stain. Twenty were positive with both OptiMal and Giemsa (Plasmodium vivax, 14; Plasmodium falciparum, 6); 10 were negative with both. The remainder were positive by OptiMal but negative by Giemsa and, therefore, were classified as equivocal. All slides were processed simultaneously, stained with berberine, and read under a fluorescent microscope. P vivax and P falciparum DNA fluoresced with berberine.
The positives and negatives by berberine concurred with the Giemsa staining. Of the 10 equivocal smears, 5 were confirmed positive by berberine. Gametocytes were easily identifiable. This test has high sensitivity and high positive predictive value and, once standardized, can be used as a potential screening and diagnostic tool.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES BABESIOSIS
PROGNOSIS CHARACTERIZATION GENERAL
- The use of the multi-organ-dysfunction score to discriminate different levels of severity in severe and complicated Plasmodium falciparum malaria.
Helbok R, Dent W, Nacher M, Lackner P, Treeprasertsuk S, Krudsood S, Wilairatana P, Silachamroon U, Looareesuwan S, Schmutzhard E.
Clinical Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
Am J Trop Med Hyg. 2005 Feb;72(2):150-4. Abstract quote
Clinical presentation of Plasmodium falciparum malaria reflects a continuum from asymptomatic to multi-organ manifestation and death. Severe malaria is defined by the World Health Organization as a qualitative variable.
We used the multi-organ dysfunction score (MODS) as a quantitative approach for severity in 29 patients with severe and complicated P. falciparum malaria to test its usefulness in discriminating different severity levels. The MODS on admission was highly correlated with the duration of symptoms after admission (r = 0.73, P < 0.001) and the serum level of tumor necrosis factor alpha (r = 0.41, P = 0.03).
In addition, the simplified MODS, based mainly on clinical findings, was also correlated with liver and renal dysfunction during hospitalization (alanine transaminase, r = 0.42, P = 0.02; blood urea nitrogen, r = 0.45, P = 0.015). A score >or= 16 was associated with significantly longer disease duration (P = 0.018). Thus, this score might provide a predictive value for morbidity in P. falciparum malaria.
TREATMENT CHARACTERIZATION GENERAL RANDOMIZED TRIALS
- An open, randomized trial of three-day treatment with artesunate combined with a standard dose of mefloquine divided over either two or three days, for acute, uncomplicated falciparum malaria.
Silachamroon U, Krudsood S, Thanachartwet W, Tangpukdee N, Leowattana W, Chalermrut K, Srivilairit S, Wilaiaratana P, Thimasarn K, Looareesuwan S.
Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand.
Southeast Asian J Trop Med Public Health. 2005 May;36(3):591-6. Abstract quote
The combination of artesunate and mefloquine is currently one of the most effective treatments for multidrug-resistant Plasmodium falciparum malaria. Simultaneous, rather than sequential treatment with the two drugs, would allow better patient compliance.
We therefore evaluated three-day treatment with artesunate combined with either 2 or 3 days of mefloquine co-administered once a day with artesunate. The study was an open, randomized trial for acute, uncomplicated falciparum malaria and was conducted at the Bangkok Hospital for Tropical Diseases. One hundred and twenty adult patients were randomized to two treatment groups. Group 1 patients received 4 mg/kg/day of artesunate for 3 days and 3 daily doses of 8.0 mg/kg/day mefloquine given with artesunate. Group 2 patients received the same dose of artesunate and the same total dose of mefloquine (25 mg/kg).
However, the mefloquine was given as 15 mg/kg on the first day and 10 mg/kg/ on the second day, again with artesunate. The baseline demographic and clinical characteristics of the patients in the two groups were similar. The cure rates for the 3-day and 2-day mefloquine regimens were 100% and 99%, respectively. There were no significant differences in either median fever clearance times (group 1=32 hours; group 2=33 hours) or mean parasite clearance times (group 1=42.3 hours; group 2=43.3 hours). Both regimens were well tolerated and there were no significant differences in the incidence of adverse effects.
Nausea or vomiting occurred in 3.8% of patients in both groups and transient dizziness occurred in 4% of group 1 and 9% of group 2 patients. These results suggest that a 3-day regimen of mefloquine administered with artesunate is effective and well tolerated. This practical regimen could improve patient compliance.
- A Randomized Comparison of Artesunate-Atovaquone-Proguanil versus Quinine in Treatment for Uncomplicated Falciparum Malaria during Pregnancy.
McGready R, Ashley EA, Moo E, Cho T, Barends M, Hutagalung R, Looareesuwan S, White NJ, Nosten F.
Shoklo Malaria Research Unit, Mae Sot, and Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, United Kingdom.
J Infect Dis. 2005 Sep 1;192(5):846-53. Epub 2005 Jul 27. Abstract quote
Background. There is no safe, practical, and effective treatment for pregnant women infected with multidrug-resistant Plasmodium falciparum.
Methods. We recruited pregnant Karen women in the second or third trimesters of pregnancy who had uncomplicated falciparum malaria for a randomized, open-label trial with a restricted sequential trial design of 7 days of supervised quinine (SQ7) versus 3 days of artesunate-atovaquone-proguanil (AAP).
Results. Eight-one pregnant women entered the study between December 2001 and July 2003; 42 were treated with SQ7 and 39 were treated with AAP. Fever, parasite clearance, and duration of anemia were significantly better with AAP; the treatment failure rate was 7 times lower (5% [2/39] vs. 37% [15/41]; relative risk, 7.1 [95% confidence interval, 1.7-29.2]; P=.001). There were no significant differences in birth weight, duration of gestation, or congenital abnormality rates in newborns or in growth and developmental parameters of infants monitored for 1 year.
Conclusion. AAP is a well-tolerated, effective, practical, but expensive treatment for multidrug-resistant falciparum malaria during the second or third trimesters of pregnancy. Despite the small number of subjects, our results add to the growing body of evidence that AAP is safe for the mother and the fetus.
- Artemisinin versus nonartemisinin combination therapy for uncomplicated malaria: randomized clinical trials from four sites in Uganda.
Yeka A, Banek K, Bakyaita N, Staedke SG, Kamya MR, Talisuna A, Kironde F, Nsobya SL, Kilian A, Slater M, Reingold A, Rosenthal PJ, Wabwire-Mangen F, Dorsey G.
Ministry of Health, Kampala, Uganda.
PLoS Med. 2005 Jul;2(7):e190. Epub 2005 Jul 26. Abstract quote
BACKGROUND: Drug resistance in Plasmodium falciparum poses a major threat to malaria control. Combination antimalarial therapy including artemisinins has been advocated recently to improve efficacy and limit the spread of resistance, but artemisinins are expensive and relatively untested in highly endemic areas. We compared artemisinin-based and other combination therapies in four districts in Uganda with varying transmission intensity.
METHODS AND FINDINGS: We enrolled 2,160 patients aged 6 mo or greater with uncomplicated falciparum malaria. Patients were randomized to receive chloroquine (CQ) + sulfadoxine-pyrimethamine (SP); amodiaquine (AQ) + SP; or AQ + artesunate (AS). Primary endpoints were the 28-d risks of parasitological failure either unadjusted or adjusted by genotyping to distinguish recrudescence from new infections. A total of 2,081 patients completed follow-up, of which 1,749 (84%) were under the age of 5 y. The risk of recrudescence after treatment with CQ + SP was high, ranging from 22% to 46% at the four sites. This risk was significantly lower (p < 0.01) after AQ + SP or AQ + AS (7%-18% and 4%-12%, respectively). Compared to AQ + SP, AQ + AS was associated with a lower risk of recrudescence but a higher risk of new infection. The overall risk of repeat therapy due to any recurrent infection (recrudescence or new infection) was similar at two sites and significantly higher for AQ + AS at the two highest transmission sites (risk differences = 15% and 16%, p < 0.003).
CONCLUSION: AQ + AS was the most efficacious regimen for preventing recrudescence, but this benefit was outweighed by an increased risk of new infection. Considering all recurrent infections, the efficacy of AQ + SP was at least as efficacious at all sites and superior to AQ + AS at the highest transmission sites. The high endemicity of malaria in Africa may impact on the efficacy of artemisinin-based combination therapy.Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
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Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
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