High Rates of Malaria Microscopy but Low Turnaround of Test-results Among Inpatients in Tertiary Care: With Delayed Initiation, Monotherapy and Incomplete Dosing of Antimalarials

Objectives:To describe the patterns of malaria diagnosis and antimalarial use: monotherapy, missed Day 1 dosing and risk-factors. Methods: Prospective cohort of consented adult inpatients on the medical and gynaecological wards of Uganda’s 1790-bed Mulago National Referral Hospital. Results: One in ve (19%, 146/762; 95% condence interval (CI): 16% to 22%) inpatients had an admitting or discharge malaria diagnosis or both. Microscopy was requested in 77% (108/141; 95% CI: 69% to 83%) of inpatients with an admitting malaria diagnosis; results were available for 46% (50/108; 95% CI: 37% to 56%), of whom 42% (21/50; 95% CI: 28% to 57%) were positive. Artesunate (AS) only (47%, 47/100; 95% CI: 37% to 57%) was the most frequently hospital-administered antimalarial followed by quinine (Q) only (23%, 95% CI: 15% to 32%). A quarter (25%, 25/100; 95% CI: 17% to 35%) of the inpatients missed their Day 1 dose of hospital-initiated antimalarials. Nearly half (47%, 95% CI: 34% to 61%) of 57 inpatients on AS and 18%(95% CI: 4% to 32%) of 28inpatients on Q missed at least one day of dosing in Days 1-3. Number of admitting diagnoses was a signicant risk-factor for missed Day 1 dosing of hospital-initiated antimalarials (OR = 2.7, 95% CI: 1.53-4.54; P-value < 0.001). Conclusions: Half the malaria microscopy results were not available; yet, the rate of testing was high. Improvement in laboratory services, procurement, prescription, dispensing and administration of antimalarials could missed for conrmed malaria cases, monotherapy and delayed doses.


Patterns of malaria diagnosis and antimalarial use
The proportions of inpatients who received antimalarials preadmission and during hospitalization were determined using, as numerator, the number of inpatients who received at least one antimalarial and, as denominator, the total number of study patients. We calculated proportions of inpatients who had malaria microscopy done and those who experienced antimalarial missed-dose days, including missed Day 1 dosing. See Appendix for details on time-to-rst-dose and parenteral-to-oral-switch of antimalarials.
We used Chi-squared tests to screen univariate-level relationships between patient-level characteristics and antimalarial use during hospitalization (yes/no); and potential patient-level risk-factors for missed Day 1 antimalarials during hospitalization. Logistic regression was used to identify risk-factors for missed Day 1 antimalarials. Results were expressed as odds ratios (ORs) with their 95% con dence intervals (CIs). Poisson CIs were used for counts below 16. Stata 14.0 [11] was used for all the analyses.
Identi cation of missed Day 1 dosing of antimalarials Among inpatients for whom an antimalarial was prescribed during hospitalization and at least one dose administered, missed Day 1 dosing was measured in two ways; i) calendar-day as proposed by Kiguba et al 2016 [3], see Appendix, and ii) 24-hour timescale using date-and-time of hospital admission and dateand-time of rst in-hospital antimalarial dose.

Missed opportunity for hospital-initiated antimalarials
Four of 25 (16%, 95% CI: 5% to 36%) inpatients with a positive malaria test did not receive in-hospital antimalarials; none of the fourdied while in hospital, see Box 1, and none had malaria-in-pregnancy.
Malaria-in-pregnancy: For both AS and Q, there was no signi cant difference in frequency of missed-dose days based on pregnancy-status, see Appendix.
Mortality among inpatients who received in-hospital antimalarials Four of 100 inpatients who received in-hospital antimalarials died during hospitalization. All four inpatients had clinically-diagnosed malaria: microscopy was requested is three inpatients, but results were not available, see Box 2.Unconscious 88-year-old female of unknown HIV-status presented with a single admitting diagnosis of severe malaria and pulse rate of 98 beats per minute. She received a prereferral intramuscular Q dose 23 hours preadmission and two Qdoses 11 hours apartafter admission. She died on Day 2 of hospitalization. The other three cases had multiple diagnoses, see Box 2.
Patient-level risk-factors for missed Day 1 dosing of antimalarials Number of admitting diagnoses was a statistically signi cant risk-factor for missed Day 1 dosing of hospital-initiated antimalarialsbased on calendar-day (OR = 2.7, 95% CI: 1.53-4.54; P-value < 0.001), see Table 6. Similar results of missed Day 1 risk-factorwere obtained based on post-admission 24-hour-delay, see Table S1.Malaria-in-pregnancy was not signi cantly relatedto missed Day 1 dosing of antimalarials.

Missed Day 1 dosing of hospital-initiated antimalarials versus length of hospital stay
Nostatistically signi cant association was observedbetween missed Day 1dosing of antimalarials and length of hospital stay (OR = 1.1, 95% CI: 0.91-1.27; P-value <0.396).Mean length of hospital stay for missed Day 1 cases was 4.7 (SD=1.7) days versus 4.2 (SD=2.5) days for non-cases. Results were returned on Day 1 with con rmed malaria parasitaemia. AL and paracetamol were prescribed on Day 2 but not dispensed. The patient was discharged on Day 3 without antimalarial treatment.

Patient 2
A 24-year-old female with unknown HIV-status was referred from a clinic where she had been treated for suspected malaria and typhoid with no improvement. She presented with poorly treated malaria and a request for microscopy for malaria parasites was made on Day 1. Results were returned on Day 2 with con rmed malaria parasitaemia. AL and paracetamol were prescribed on Day 2 but not dispensedand the patient was discharged on Day 2 without antimalarial treatment.

Patient 3
A 44-year-old HIV-negative male was transferred from a referral hospital. He presented with an admitting diagnosis of chronic lymphocytic leukaemia and con rmed malaria parasitaemia by microscopy. No fresh request for malaria microscopy was made during the current admission. The patient did not receive any antimalarial treatment prescription and/or administration both prior to admission and throughout the current hospitalization. He was transferred to Uganda Cancer Institute on Day 3.

Patient 4
A 43-year-old HIV-positive female with history of DM and receiving second-line antiretroviral therapy, ART (tenofovir, lamivudine, lopinavir/ritonavir) and co-trimoxazole presented with an admitting diagnosis of colon cancer. Microscopy for malaria parasites was requested on Day 2 and results were returned the same day with con rmed malaria parasitaemia. No antimalarial treatment was prescribed, dispensed or administered during hospitalization though the patient continued to receive her ARTP and co-trimoxazole. The patient was transferred to Uganda Cancer Institute on Day 17.

Discussion
Malaria microscopy was requested in 77% of inpatients with an admitting malaria diagnosis, similar to estimates for the public sector (80%) in moderate-to high-transmission countries in sub-Saharan Africa (SSA) [1]. Unfortunately, only half the microscopy results were available to guide appropriate antimalarial treatment. Thus, despite decent microscopy rates, healthcare professionals still rely on clinical judgement to treat half the suspected malaria cases. Clinical judgement increases the risk of unnecessary antimalarial treatment and, in turn, depletes antimalarial stocks for inpatients who truly need them; and increases the incidence of associated adverse drug reactions and drug resistance [2]. Seven in ten inpatients with suspected non-pregnancy-related malaria tested negative for malaria and would therefore not need antimalarials; compared with only two in ten inpatients with suspected malaria-in-pregnancy.
The value of a con rmed malaria diagnosis depends on prompt availability of parasitology results and whether the clinician uses the results to decide how to manage the patient. Malaria negative test-results as con rmed by microscopy -the gold standard -should prompt clinicians to examine patients for other causes of illness and treat them accordingly [2]. However, the interpretation of negative microscopy results should take into account the high rates of antimalarial pre-treatment, which was as high as one in three admitted patients with suspected malaria in this patient cohort. A rapid diagnostic test (RDT), in addition to microscopy, could be used to detect the HRP2 malaria antigen in patients who recently received antimalarials and whose blood lms are, thus, likely to show no malaria parasitaemia [2]. RDTs can give positive results for up to 1-month after parasite clearance [2].
One in six cases of con rmed malaria did not receive antimalarials during the current hospitalization, which raises concern over the safety of inpatient care at this tertiary care hospital. Poor coordination between the laboratory and clinicians is likely, which is exacerbated by high inpatient loads of up to 80 admissions in wards with o cial bed capacity of 54 [3]. Introducing an integrated electronic health record (EHR) system to track inpatient care could signi cantly improve the ow of information between different hospital departments and, in so doing, promote e cient clinical management of inpatients [12].
One in four inpatients who received at least one in-hospital dose of prescribed antimalarials missed the rst day of their antimalarials, which is relatively frequent. Also, monotherapy and incomplete dosing primarily associated with injectable AS and Q were common, possibly fuelled by observed disparities in prescribed, dispensed and administered antimalarials -similar to observations made elsewhere [8,10]. Possible reasons for these system lapses include; i) drug stock-outs, ii) poor communication between clinician and patient/caregiver and, iii) work overload [3]. The hospital should improve its stock forecasting for in-demand antimalarials, continue to promote intern-pharmacist-led bedside dispensing to reduce the clinicians' workload during drug administration and improve supervision of junior and midlevel clinicians to promote accountability to inpatients and the hospital [3].
Each additional admitting diagnosis increases by more than two-fold the odds of missed Day 1 dosing of prescribed antimalarials, which underlines the need for prompt availability of malaria test-results to promote the timely initiation of antimalarials. Prompt and complete antimalarial treatment rapidly eliminates malaria parasites from a patient's bloodstream [13]. Patients with severe malaria should access timely appropriate antimalarials, avoid antimalarial monotherapy and complete full courses of prescribed antimalarials to promote therapeutic success, reduce malaria-related morbidity and mortality, and prevent the emergence and spread of drug resistance [7][8][9].
Inpatients with an admitting malaria-in-pregnancy diagnosis seemed more likely to have a microscopically-con rmed malaria diagnosis than inpatients with other admitting malaria diagnoses.
This comparative advantage at diagnosis did not translate into better antimalarial treatment because no pregnancy-related difference was observed in the prescription, dispensing and administration of antimalarials. Improvement in the antimalarial medication-use-cycle should target systemic weaknesses.
Unlike Q, the hospital frequently encounters drug stock-outs of in-demand, free-of-charge AS and AL, which inpatients must purchase from private community pharmacies to prevent lapses in prescribed treatment. Drugs bought from private community pharmacies are not recorded as dispensed in the hospital register [3], which explains why the reported number of inpatients with administered AS and AL exceeds the number of inpatients to whom these two drugs are dispensed. AS and AL are more in demand than Q because; i) AS is the drug of choice for its faster parasite clearance, less tedious administration regime, and safer pro le and, ii) AL is administered after both injectable AS and Q as the continuation of antimalarial treatment in severe malaria [2].
Death could be attributed to severe malaria and/or quinine-related treatment in the 88-year-old female with a single admitting severe malaria diagnosis. The caveat to this malaria-related attribution is malaria based on clinical judgement only (in the absence of microscopy results), unknown HIV-serostatus, advanced age, unknown random blood sugar levels and other comorbidities -especially cardiovascular comorbidities. That notwithstanding, Q was poorly administered at intervals of 25 hours (between rst and second doses) and 11 hours (between second and third doses). Yet, 8-hourly intervals of injectable Q administration for at least 24 hours are recommended until the patient is able to take oral medication [2].
The unconsciousness manifested in this inpatient is a known key sign of hypoglycaemia in severe falciparum malaria and carries a high risk of mortality [2]. Unfortunately, hypoglycaemia can result from both severe malaria and quinine-induced hyperinsulinaemia. Thus, blood sugar levels should be checked frequently in severe malaria inpatients who receive Q [2]. Also, this inpatient had tachycardia which could have resulted from Q use and/or hypoglyaemia. With hindsight, this elderly inpatient should have been treated with injectable AS instead, although the frequent unavailability of in-demand AS, and its associated higher cost, often dictates treatment with Q. This fatal case of suspected severe malaria underpins the need for the rapid turnaround of microscopy test-results and the hospital's investment in routine random blood sugar testing to improve the clinical management of inpatients with severe malaria.
In conclusion, half the malaria microscopy results were not available to guide the clinical management of malaria despite that the rate of testing was high. Laboratory services should improve to promote the treatment of malaria based on con rmed diagnosis as opposed to clinical judgement only, which could reduce the unnecessary use of antimalarials. System-level improvement is required in the procurement, prescription, dispensing and administration of antimalarials to curb the rampant missed opportunities for antimalarial treatment, monotherapy especially with injectable antimalarials and delayed/missed antimalarial doses.
The study's limitations have been reported elsewhere [3]. Brie y, the study was conducted at Uganda's National Referral and Teaching Hospital and the results might not be generalizable to facilities with lower calibres of inpatient care. Also, antimalarials that were purchased from private community pharmacies were not documented as dispensed in the hospital register so we obtained this dispensing information by interviewing the inpatients and/or their caregivers [3].

Declarations
Ethics approval and consent to participate:

Consent for publication:
Consent to publish this work was sought during the informed consent process.
Availability of data and materials: The dataset for this publication is available on reasonable request from the corresponding author.
Competing interests: SMB. holds GSK shares. RK and CK have nothing to declare.