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    Total clinic attendance and patients recruited to study by malaria test results (microscopy, RDT, PCR) and antimalarial treatment prescribed.

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Accuracy of Malaria Diagnosis by Microscopy, Rapid Diagnostic Test, and PCR Methods and Evidence of Antimalarial Overprescription in Non-Severe Febrile Patients in Two Tanzanian Hospitals

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  • 1 Virology and Microbiology Laboratories, Epidemiology and Clinical Departments, National Institute for Infectious Diseases Lazzaro Spallanzani (INMI), Via Portuense 292, 00149 Rome, Italy; Public Health Laboratory–Ivo De Carneri Pemba, Chake Chake Hospital, Pemba, Zanzibar; Tosamaganga Hospital, United Republic of Tanzania; National Institute for Medical Research, Dar es Salaam, United Republic of Tanzania; Italian Cooperation, Italian Ministry of Foreign Affairs, Rome Italy

The study was aimed to evaluate the malaria over/underdiagnosis and over/underprescription of antimalarial drugs. Between February and March 2007 blood samples were collected from 336 non-severe febrile outpatients attended in two peripheral Tanzanian hospitals. Microscopy and a rapid diagnostic test (RDT) were done locally and the accuracy evaluated by qualitative polymerase chain reaction (PCR) for Plasmodium spp. The testing was performed at National Institute for Infectious Diseases Lazzaro Spallanzani (INMI), Rome, Italy. As a result of PCR, we identified 26 malaria cases out of 336 (7.7%) patients. Microscopy and RDT accuracies were 93.5% and 97.6%, respectively. Overprescription and underdiagnosis rates were 29.3% and 30.8%, respectively. On-field training, clinical management of febrile illness, and malaria microscopy in remote settings should be considered.

INTRODUCTION

The frequency of febrile illness in sub-Saharan Africa is very high with demographic and health surveys reporting that up to 40% of children experienced a febrile illness in the previous two weeks. Malaria accounts for over 30% of the national burden of disease and loss of productivity in Tanzania, where the disease is endemic and characterized by a pattern of low-moderate intensity of malaria transmission.1 The accuracy of malaria clinical diagnosis is limited by the low specificity of symptoms and signs of malaria.24 In Africa, 70% of fever cases in children are diagnosed at home and presumptive antimalarial treatment of any fever with no obvious alternative cause is widely practiced.59

Artemisinin-based combination therapy (ACT) is highly efficacious and has the potential to delay the spread of increasing parasite resistance to existing monotherapies. On the basis of these principles, ACT is recommended as first line therapy for uncomplicated malaria throughout Africa. Particularly, artesunate-amodiaquine has been recommended in Zanzibar since 2002 and artemether-lumefantrine in Tanzania since 2005. 1013 Since 2003, the Tanzania Ministry of Health adopted an implementation strategy to promote nationwide usage of insecticide treated mosquito nets. 1,14,15 In the Iringa region, data provided by the National Malaria Control Program (NMCP-2004), reported that 31.7% of the outpatient department attendances, 21.8% of the patients admissions, and 19.5% of inpatients death are attributed to malaria. Differently, in the Zanzibar Islands, a favorable malaria reduction rate in outpatients was reported by microscopy: from a 40.7% in 2003 to a 3.0% prevalence rate in 2006 (Ali AS, unpublished data).

The aim of this study is to estimate the rates of malaria underdiagnosis and overdiagnosis, the rates of underprescription and overprescription of antimalarial treatment in patients affected by non-severe febrile syndrome in two Tanzanian hospitals using a qualitative polymerase chain reaction (PCR) as “the gold standard” for diagnosis of Plasmodium spp.

METHODS

Study areas.

The study was conducted in two peripheral hospitals of the United Republic of Tanzania. In the Chake Chake hospital, in Pemba Island, the study was carried out from February 9, 2007 to March 12, 2007 during the dry season jointly with the Public Health Laboratory Ivo De Carneri (PHL-IdC). In the Tosamaganga missionary hospital, in the Iringa region, the study was conducted from March 3, 2007 to March 29, 2007 during the wet season jointly with the CUAMM-Doctors with Africa—an Italian non-governmental organization (NGO).

Study design.

A cross-sectional observational study was conducted in the outpatient departments of the Chake Chake and Tosamaganga hospitals. Inclusion criteria were an age ≥ 1 year and a body temperature ≥ 38°C for a period of less than 10 days. Exclusion criteria were previous antimalarial treatment, the presence at physical examination of signs of a severe disease, including complicated falciparum malaria, according to the World Health Organization (WHO) definition given in 2001. 16 Patients affected by mental illness, by a clinical picture explicit for diagnosis of measles, chickenpox, otitis, infected wounds, or chest x-ray documented pneumonia, were excluded.

Ethical committee.

Ethical approval was obtained from the National Institute of Infectious Diseases (INMI) Lazzaro Spallanzani in Italy, from the National Institute for Medical Research (NIMR) in Tanzania, and from the Ministry of Health and Social Welfare in Zanzibar.

Protocol procedure.

An easy-to-read and friendly questionnaire was provided for the collection of epidemiologic and clinical data. A physical examination with a clinical note of any reported sign or symptom, including final diagnosis and drug prescription, was requested to the local medical officer for each enrolled patient. Microscopy smears and rapid diagnostic tests (RDT) for malaria were performed, read, and recorded daily by the hospital laboratory technician. They were read before or immediately after the end of the consultation. A quality assurance system for laboratory services was established in all districts and involved training and support with malaria blood slide reading.1

The protocol procedures and the study collaborators did not change the current standard of care of each facility. After receiving complete information in Kiswahili about the collection of biological samples for research purposes, all consenting adult patients and parents or tutors of patients less than 18 years of age, signed the informed consent.

Laboratory investigations.

A finger-prick blood sample was collected from each enrolled patient. This sample was used to prepare thick and thin smears and for testing with the ParaHIT f test (Span Diagnostic Ltd., Surat, India). The ParaHIT f dipstick test was performed according to the manufacturer’s instructions. The test detects Plasmodium falciparum–specific histidine-rich protein II. Thick and thin blood films were prepared and stained with Giemsa following WHO standards. 17 A slide was considered positive if at least one asexual form was detected. Blood parasite density was determined from the thick films by counting the number of parasites against 200 white blood cells and assuming that each subject had 8,000 white blood cells/μL of blood. A minimum of 200 fields were examined before declaring slides negative. From each enrolled patient, 1 mL of venous blood was also collected into a vial containing EDTA. Five drops of venous blood were absorbed on filter paper collection cards (S&S 903, Schleicher and Schuell, Dassel, Germany).

At the end of the two collection phases, all samples were dispatched at the appropriate temperatures to the INMI and venous blood samples were processed for detection of the four human malaria species by PCR assay. Approximately 200 μL of blood were used to extract DNA using BioRobot MDx and QIAamp DNA Blood BioRobot MDx Kit (QIAGEN, Germany). For 16 patients with no blood aliquot available, dried blood spots were used to extract DNA with QIAamp DNA Mini Kit (QIAGEN). Detection and identification of Plasmodium species were performed using a nested PCR. 18 A PCR for β-globin was conducted in parallel to assess suitability for amplification of the extracted DNA. 19 The sizes of the products were estimated after electrophoresis on 2% ethidium bromide stained agarose gel under ultraviolet illumination.

Data analysis.

The rate of slide positive PCR-negative malaria patients on the total of PCR-negative patients was considered as overdiagnosis; the rate of slide negative PCR-positive malaria patients on the total of malaria PCR positive patients was considered as underdiagnosis; the rate of malaria slide negative treated patients on the total of malaria slide-negative patients was considered as overprescription; and the rate of slide positive untreated patients on the total of slide positive patients was considered as underprescription. Sensitivity, specificity, and accuracy were calculated from microscopy and RDT results compared with PCR results.

Data were entered, processed, and analyzed using SPSS software package (SPSS 15.0 for Windows, Chicago, IL). Frequencies were calculated and compared with χ2 test and media were compared with the Mann–Whitney test.

RESULTS

During the study period, 1,800 outpatients were attended in the two sites: 960 patients (53.3%) were screened at Tosamaganga Hospital and 840 patients (46.7%) were screened at Chake Chake Hospital; 1,463 patients (81.3%) were excluded as not fulfilling the study enrollment criteria; 337 patients (18.3%) were eligible and 336 patients (18.7%) were recruited (Figure 1). All recruited patients were tested by microscopy, RDT, and PCR.

One hundred and seventy patients were adults (50.6%), equally represented in the two study sites. Children < 5 years of age were 92 out of 336 patients (27.4%) and were more represented in the Chake Chake Hospital (60 patients, 65.2%). In both sites female patients were slightly more represented than males. More frequently reported symptoms were headache (46.7%), cough (41.4%), joint pain (35.4%), and vomiting (22.3%). Previous pharmacologic treatments were investigated: 103 patients (30.7%) had received paracetamol and 21 patients (6.3%) completed an antibiotic course. Penicillin derivatives were prescribed in 11 out of 21 cases (52.4%), whereas co-trimoxazole was prescribed in 4 cases (19.0%). At clinical consultation, an antimalarial treatment was prescribed to 115 out of 336 patients (34.2%). Particularly, an ACT regimen was prescribed to 77 out of 115 patients (67.0%); an antibiotic course was prescribed to 205 febrile patients (61.0%), and paracetamol only was given to 6 patients (1.8%) (Tables 1 and 2).

Malaria diagnosis was confirmed by microscopy and by RDT in 32 cases (9.5%) and in 18 cases (5.4%), respectively. Of the 32 patients positive at microscopy, 15 cases were confirmed by RDT, whereas among the 304 patients with negative blood slide at microscopy 3 cases of malaria were identified by RDT. Plasmodium falciparum was observed in all 32 patients with positive blood slides. The PCR assay showed 26 cases (7.7%) of malaria infections. Particularly, at the Chake Chake hospital in Pemba the prevalence rate (4.0%) was lower than that in the Tosamaganga rural hospital (11.7%) (P = 0.016). The PCR assay confirmed 18 out of 32 P. falciparum cases (56.3%) observed by microscopy, and all cases (18, 100%) reported by RDT. Conversely, the PCR assay confirmed 3 malaria cases previously identified only by microscopy and added 5 new cases not previously diagnosed by microscopy and RDT (19.2%). Of these cases, one case of Plasmodium malariae in the Chake Chake Hospital was diagnosed by PCR. No mixed infection was reported. The parasite density was higher in patients with a PCR-confirmed malaria (1832 ± 3653 parasites/μL) compared with patients without PCR-confirmed malaria diagnosis (406 ± 185 parasites/μL), but the difference did not attain a statistical significance, P = 0.152.

Table 3 shows malaria diagnosis accuracy of microscopy and RDT methods versus PCR assay. The different accuracies of microscopy compared with RDT (93.5% versus 97.6%, respectively) were substantially a result of the low positive predictive value (56.3%) of microscopy in detecting malaria parasites in the patient’s blood slide.

Among the 304 patients with a negative microscopy, 89 received a clinically-based antimalarial treatment: over-prescription, 29.3% (Table 3). Among the 32 patients with a positive microscopy, 6 individuals were not treated with anti-malarials: underprescription, 18.8% (Table 4). Of the patients, 3 cases were treated with antibiotics, 1 case with paracetamol and 2 cases received no drug. Antibiotics were prescribed to 7 out of 32 (21.9%) patients with a slide positive for malaria and to 198 out of 304 (65.1%) patients with a negative slide (P < 0.001); this difference was even higher in children under 5 years of age (16.7% versus 78.8%, P < 0.001).

Table 5 shows data on the age distribution of malaria prevalence in the two study sites according to different diagnosis methods. Most adults had a clinically-based only diagnosis, where as the proportion of patients with clinically-based malaria confirmed by microscopy was higher among patients < 5 years of age. Particularly, 28 out of 92 under fives (30.4%) were clinically diagnosed with malaria: this was confirmed by microscopy, RDT, and PCR in 13.0%, 5.4%, and 8.7% of the cases, respectively.

DISCUSSION

Malaria is the single most common diagnosis in several hospitals in Africa; the 32–96% of the febrile patients have an antimalarial treatment prescribed on clinically-based approach. 5,6,8,9 Such drug policy is recommended in the specific literature on the clinical management of malaria infections in patients < 5 years of age resident in endemic areas with a high transmission rate. 20

This cross-sectional survey has reported a 7.7% prevalence rate of malaria infection by PCR assay in non-severe febrile outpatients at two site studies. Particularly, at the Chake Chake hospital in Pemba the prevalence rate (4.0%) was lower than that in the Tosamaganga rural hospital (11.7%). The Chake Chake governmental hospital is located in the Pemba Island of the Zanzibar Republic where a perennial stable transmission of malaria is reported. 21 The climate is characterized by two distinct rainy seasons. Heavy rains (Masika) fall between March and May and a shorter rainy period (Vuli) takes place from October to December. The study was carried out during the dry season. The Tosamaganga missionary hospital is located in the Iringa rural district of the United Republic of Tanzania; the study was conducted during the wet season. Iringa rural is located in the south-west of Tanzania and is characterized by a mountainous and undulating topography, reaching in Tosamaganga around 1,500 m of altitude. Iringa rural is characterized by unstable malaria transmission prone to outbreak of disease, mainly during the rainy season that occurs between February and April. In a study 22 carried out in six villages located at different altitudes in central Tanzania to determine malaria parasitaemia and transmission levels, the higher malaria prevalence was observed in villages at lower (< 1000 m) than at intermediate (1000–1500 m) or higher (> 1500 m) altitudes.

Prevalence rates observed in this study reflect the pattern of malaria low-moderate transmission in the two surveyed areas. The lower prevalence rate found in Pemba compared with that of Tosamaganga can be explained with the previously described geographic and seasonal differences between the two study sites. Moreover, the prevalence found in Pemba is consistent with the 3.0% Zanzibar malaria blood slide positive prevalence reported by Zanzibar Malaria Control Program in 2006. 21 At Tosamaganga, a 17.2% and 11.7% prevalence rate of P. falciparum malaria by microscopy and by PCR was reported among general population, respectively (Table 5). whereas a 34.4% and a 18.8% of prevalence rate by microscopy and by PCR was reported among under five patients, respectively. Children < 5 years of age are most likely to suffer from the severe effects of malaria because they have not developed sufficient naturally acquired immunity to the parasite. A severe infection can kill a child within hours. 23 Both microscopy and PCR-based malaria prevalence rates in the general population and in under fives are lower than those expected during the rainy season and reported in 2004 by NMCP in the Iringa region. In this survey the proportion of outpatient cases attributed to malaria in general populations and in under fives was 31.7% and 37.7%, respectively. Such discordance could be explained by the implementation of the new ACT-based drug and vector control policies since 2005, and by the occurrence of a delayed rainy season in Iringa.1

As cited in the results section, the parasite density was higher in patients with PCR-confirmed malaria compared with patients without PCR-confirmed malaria diagnosis. In general, there is good agreement between PCR and microscopy at relatively high parasite densities (> 500 parasites/μL). In a study by Coleman and others 24 comparing PCR and microscopy for the detection of malaria cases in Thailand, a high proportion of all microscope-positive samples were negative by PCR, and a high proportion of PCR-positive samples were negative by microscopy. Ninety-eight percent of the microscope positive, PCR-negative samples had fewer than 250 parasites/μL blood. Barker and others 25 carefully analyzed discrepancies between microscopy and PCR, and although true false negative PCR results did occur, the majority of discrepancies resulted from problems with microscopy.

In this survey using the PCR assay as the reference gold standard, the ParaHit f shares the same sensitivity rate of the microscopy reading. Nevertheless, the accuracy of the malaria diagnosis by ParaHit f is higher (97.6%) than provided by microscopy (93.5%). It is substantially a result of the low positive predictive value of the microscopy. Conversely, the few cases of negative RDT found to be positive by PCR (69.2% sensitivity) could be related to a fluctuant low parasite density (Table 3). Marx and others 26 in the systematic review on the accuracy of RDT for malaria in returning travelers, indicates that RDT, despite a low sensitivity, will lead to the detection of most clinically relevant P. falciparum cases, with considerably better accuracy than that expected from routine microscopy.

In our survey both malaria underdiagnosis (30.8%) and overprescription (29.3%) rates are relevant and they appear to be consistent with specific literature data. A randomized trial that compared the use of malaria microscopy to RDT in Tanzania found that more than half of patients with negative RDT results were prescribed an antimalarial. 27 As previously described by Reyburn and others,8 our survey of malaria diagnosis was not supported by microscopy reading in 57.1% of patients < 5 years of age, whereas an antimalarial was prescribed on a clinically-based approach only in 71.2% of adults. The lower overprescription rate in under fives underlines the higher clinical appropriateness of antimalarial drug prescription in the management of febrile children compared with adults. However, the need of clinically-based algorithms for the management of febrile syndromes has to be considered. The overuse of antimalarial drugs in low-moderate transmission sites is no longer safe and sustainable from a clinical and economical point of view.

Our experience confirmed that RDT in conjunction with microscopy should improve the diagnosis of malaria. However, RDT use should be considered as more cost-effective in the areas characterized by high-moderate intensity malaria transmission and in situations where health services are deficient or absent. 26

Before drawing final conclusions, a few limits are to be underlined. First, this is a cross-sectional study and neither longitudinal follow-up nor clinical outcome of febrile patients was included in the study protocol. Second, the target population of the study was the non-severe febrile patients older than one year, thus serious malaria infections were not included in our study design.

Overall, the implications of this study are clinically relevant. First, the mentioned data describe a changing malaria epidemiology in these two rural areas of Tanzania, where other differential etiologic agents involved in the occurrence of febrile syndromes should be considered by clinicians. Second, a laboratory confirmation of malaria diagnosis is strongly needed to provide adequate clinical management of the patient. Third, in the periodical malaria sheets reported by local health authorities, true malaria cases only should be included to figure the changing trend in malaria incidence rate.

Finally, in the two peripheral health facilities the study evidenced a relatively high rate of antimalarial overprescription that confirms the global alert to the potential surging prevalence of genotypic resistance of P. falciparum to the current used ACT regimens. Despite the mentioned antimalarial overprescription in Pemba, our data confirm that the malaria control in Zanzibar appears to be a short-term achievable goal. Nevertheless, in Tanzania mainland monitoring of malaria drug resistance is to be recognized as a first-line priority in public health.

Table 1

Characteristics of the population

Table 1
Table 2

Distribution of clinical symptoms and treatment characteristics

Table 2
Table 3

Malaria diagnosis accuracy of microscopy and RDT vs. PCR assay*

Table 3
Table 4

Underdiagnosis and overdiagnosis, underprescription and overprescription rates in all population and in the two sites

All patientsTosamagangaPemba
Overdiagnosis14/296 (4.7%)14/130 (10.8%)0/166 (0.0%)
Underdiagnosis8/26 (30.8%)5/19 (26.3%)3/7 (42.9%)
Overprescription89/304 (29.3%)54/135 (40.0%)35/169 (20.7%)
Underprescription6/32 (18.8%)5/28 (17.9%)1/4 (25%)
Table 5

Malaria diagnosis according to age and to different diagnosis methods in the two sites

Clinically-based diagnosis n° (%)Microscopy-based diagnosis n° (%)RDT-based diagnosis n° (%)PCR-based diagnosis n° (%)
All patientsPembaTosamagangaBoth sitesPembaTosamagangaBoth sitesPembaTosamagangaBoth sitesPembaTosamagangaBoth sites
Age < 59210 (10.9)18 (19.5)28 (30.4)1 (1.0)11 (12.0)12 (13.0)1 (1.1)4 (4.3)5 (5.4)2 (2.2)6 (6.5)8 (8.7)
5 ≤ age < 15744 (5.4)24 (32.4)28 (37.8)0 (0.0)3 (4.1)3 (4.1)0 (0.0)4 (5.4)4 (5.4)1 (1.4)4 (5.4)5 (6.8)
Age ≥ 1517024 (14.1)35 (20.6)59 (34.7)3 (1.8)14 (8.2)17 (10.0)3 (1.8)6 (3.5)9 (5.3)4 (2.3)9 (5.3)13 (7.6)
All patients33638 (11.3)77 (22.9)115 (34.2)4 (1.2)28 (8.3)32 (9.5)4 (1.2)14 (4.2)18 (5.4)7 (2.0)19 (5.7)26 (7.7)
Figure 1.
Figure 1.

Total clinic attendance and patients recruited to study by malaria test results (microscopy, RDT, PCR) and antimalarial treatment prescribed.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 80, 5; 10.4269/ajtmh.2009.80.712

*

Address correspondence to Nazario Bevilacqua, National Institute for Infectious Diseases Lazzaro Spallanzani, Via Portuense 292, 00149 Rome, Italy. E-mail: bevilacqua@inmi.it

Authors’ addresses: Emanuele Nicastri, Monica Sañé Schepisi, Maria G. Paglia, Silvia Meschi, Antonino Di Caro, Maria R. Capobianchi, and Giuseppe Ippolito, National Institute for Infectious Diseases Lazzaro Spallanzani, Via Portuense 292, 00149 Rome, Italy. Nazario Bevilacqua, National Institute for Infectious Diseases Lazzaro Spallanzani, Via Portuense 292, 00149 Rome, Italy, Tel: +39 06 55170465, Fax: +39 06 55170413, E-mail: bevilacqua@inmi.it. Shaali M. Ame and Jape A. Mohamed, Public Health Laboratory–Ivo De Carneri, P.O. Box 122, Chake Chake, Pemba Island, Zanzibar, Tanzania. Sabina Mangi and Robert Fumakule, Tosamaganga Hospital, Iringa, P.O. Box 11, United Republic of Tanzania. Andrew Kitua, National Institute for Medical Research General Director, Dar es Salaam, United Republic of Tanzania. Fabrizio Molteni and Vincenzo Racalbuto, Italian Cooperation, Italian Ministry of Foreign Affairs, Rome, Italy.

Acknowledgments: We thank the Ministry of Health of United Republic of Tanzania and the Ministry of Health of Zanzibar for allowing the access to malaria patients and the patients for participating in the study. The National Institute for Infectious Diseases L. Spallanzani (INMI) is grateful to Dr. Valerie D’Acremont for helpful discussions and constructive advises. The American Society of Tropical Medicine and Hygiene (ASTMH) assisted with publication expenses.

Financial support: This work was part of the activities carried out by the Programme Aid 8282 in Tanzania, funded by the Italian Cooperation and Ministry of Foreign Affairs of Italy. The American Society of Tropical Medicine and Hygiene (ASTMH) assisted with publication expenses.

REFERENCES

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    Ministry of Health and Social Welfare of United Republic of Tanzania, 2002. National Malaria Medium Term Strategic Plan 2002–2007, Government of the United Republic of Tanzania, 2002 (Malaria Control Series).

  • 2

    Chandramohan D, Jaffar S, Greenwood B, 2002. Use of clinical algorithms for diagnosing malaria. Trop Med Int Health 7 :45–52.

  • 3

    Kallander K, Nsungwa-Sabiiti J, Peterson S, 2004. Symptom overlap for malaria and pneumonia-policy implications for home management strategies. Acta Trop 90 :211–214.

    • Search Google Scholar
    • Export Citation
  • 4

    Mwangi TW, Mohammed M, Dayo H, Snow RW, Marsh K, 2005. Clinical algorithms for malaria diagnosis lack utility among people of different age groups. Trop Med Int Health 10 :530–536.

    • Search Google Scholar
    • Export Citation
  • 5

    Amexo M, Tolhurst R, Barnish G, Bates I, 2004. Malaria misdiagnosis: effects on the poor and vulnerable. Lancet 364 :1896–1898.

  • 6

    Barat L, Chipipa J, Kolczac M, Sukwa T, 1999. Does the availability of blood slide microscopy for malaria at health centers improve the management of persons with fever in Zambia? Am J Trop Med Hyg 60 :1024–1030.

    • Search Google Scholar
    • Export Citation
  • 7

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