XRD Analysis

The adoption of combination therapies in several countries is accompanied by the expression, in parasites, of genetic mutations supposedly associated with drug resistance (Berzosa et al., 2017).

The high preponderance of P. falciparum genetic mutation associated with resistance to antimalarial drugs in our study does not effectively translates into functional phenotypes since further post-treatment management of patients in endemic area usually results in recovery.

Ascertaining that such resistance is mechanistically an outright drug resistant process which involves efficient and effectively expressed alternative form of genes as genetic phenotypes is difficult. If the high gene polymorphism levels observed in our study indeed translate into functionally effective phenotypes, this would have dire consequences for public health in our study area and other endemic regions. Although the likelihood is that parasites carrying mutant genes are less likely to be as fit compared with the wild type(Petersen et al., 2011), there is the possibility that they can alter the physiologic steady state of the host. The question is whether mutant plasmodium could influence the stress hormones and the inflammatory components of the immune system in a manner that translates into clinical treatment failure.

In this study, the parasite load, percentage of samples with mutations and average number of mutant alleles per patient were higher in treated than untreated group. The heightened parasitaemia and parasite mutations despite treatment seen in our study as also previously reported (Dondorp et al. 2009; White, 2004) alone may not be the only explanation for patient unwellness because our data also showed that parasite load and type (wild type and mutants) can result in sustained stressor factors (cortisol and TNF-α) elaboration despite treatment. In addition, therapeutic intervention with ACT, in particular, was shown to increase stressor factors.

138

Taken together these interacting factors may in part, account for patient unwellness despite treatment. This condition could result from treatment-induced altered internal environmental factors, which could create a picture of (i) enhanced proliferation of resistant genes, (ii) sustained proinflammation and (iii) heightened stressor conditions meted by stress hormones culminating in persistent post-treatment unwellness. The pattern of elevated TNF-α and even IL-12, although not significantly increased, is such that drives malaria infection course in the direction of proinflammation which is sustained after treatment and may account for the post-treatment complaints. Other than the proinflammatory cytokine profile pattern, the elevated values of post-treatment proinflammatory cytokines compared with control values in healthy individuals reveals a probable opportunity for heightened effects which could mete out those unwellness consequences associated with persistent malaria.

The decreased levels of IL-10 observed in treated patients has unique implication because as a cytokine principally derived from Th2 cells, it is an inhibitory factor which, under normal circumstances, would impair the sustained build-up of proinflammatory cytokines at the recovery phase of clinical malaria. In addition, when its elaboration is compromised as exhibited here, its ability to turn off macrophage elaboration of IL-12 could be impaired leading to protracted and sustained proinflammatory situation. Closely connected with this is the implication of the post-treatment impairment of the elaboration of TGF-β because of its intrinsic role to induce the development and propagation of regulatory T-cells (T-reg cells) which in turn induct CD4+-T-cell development from nạve T-CD4+-T-cells(Abel et al., 2012). The impairment of CD4+ T-CD4+-T-cells will clearly result in compromised elaboration of IL-10 thus causing a situation of persistence of proinflammatory cytokine expression. On basis of those variations that exist in steady state, the expression of impaired IL-10 will be variable and this could account for the various cases of

139

“usually sick” malaria cases that exhibit protracted symptoms of malaria illness in endemic areas. Although uncertain, it would appear that the observed negative correlation between parasitaemia and IL-10 elaboration is a revelation of parasite direct effect while Figure 21 shows the attenuating effect of drug used during treatment and pathophysiologic change in IL-10 elaboration. Optimization of IFN-γ production is needed in patients with non-severe infection from endemic area for evasion of acute phase of symptoms .Also, the decreased level of IFN- γ reported is of importance because of its pivotal role in the activation of macrophages, which is needed for plasmodium clearance. Taken together, these events could account for chronic progressive malaria disease, which can be mistakenly attributed to drug resistance. Although the role of chronic stress, as typified by our reported heightened cortisol levels, in relation to the steady state of the immune system is unclear, previous studies have reported both favorable and unfavorable events associated with the immune response in related conditions(Coutinho and Chapman, 2011; Padgett and Glaser, 2003).

Our findings showed an evidence of slight negative correlation between post- and pre-treatment parasitaemia and corticosteroid levels without a statistically significant difference with treatment, thus, revealing the impactful nature of corticosteroids. Corticosteroids are readily bound to their receptors on cells in a biphasic, concentration-dependent manner (DeRijk et al., 2002; Müller et al., 2002) . The implication of this phasic binding potential is likely to mete differential protracted action on patients and this could explain the differences in post-treatment unwellness exhibited by malaria patients. Expectedly, corticosteroids should downregulate inflammatory cytokine (TNF-α) elaboration but in the case of malaria infection, patients’ sera show the reverse, which cannot be ignored considering the post-treatment complaints of illness. Also, corticosteroids may have a role for delayed immune clearance of malaria on one hand and an

140

impaired elaboration of IL-10 on the other hand, resulting in unwanted sustained inflammatory condition. This is understandable if one considers the role of IL-10 in proinflammatory cytokine impairment. This perspective may provide explanation for carefully controlled use if not total discontinuity of corticosteroids in cerebral malaria therapy. The assessment of the recovery of P.

falciparum infected patients from malaria and the pathophysiologic consequences of drug on treated compared with untreated patients showed a compelling evidence of drug-induced consequences manifesting as (i) parasite genetic mutation, (ii) perpetuation of stressor factors and proinflammatory conditions, and (iii) impairment of regulatory cytokine functions. This combination of factors may arguably account for the post-treatment malaria-like-illness commonly designated as drug-resistant malaria instead of ACT-syndrome.

Considering that samples used were from clinical sources, the observed variation in the levels of individual cytokines between patients and control groups could have been impacted by some confounding factors such as time of sample collection, time course of illness and the disease status of individual. This study could further be validated by conducting similar experiments using in-vitro methods in malaria culture medium to take care of the limitations of confounding factors associated with clinical samples and to further validate the outcome of the in vivo methods. The power of the study would have been stronger with a bigger sample size;

nevertheless a strong pattern established was the more important with a smaller sample and could be investigated further in future research.

141 5.3 CONTRIBUTIONS TO KNOWLEDGE

1. New Pfmdr1 polymorphisms of P. falciparum that could affect future sensitivity of antimalarial medicine were identified

2. The study showed a reduction in prevalence of chloroquine resistance genes and absence of validated artemisinin resistance mutations suggestive of a possible reversal to chloroquine sensitivity and current efficacy of artemisinin in the treatment of malaria in the study area 3. Evidence that treatment related changes in the immune and endocrine response of the host which may be responsible for the pathophysiologic manifestation associated with malaria was established

4. The research showed that drug induced pathophysiologic consequences manifesting as post-treatment malaria-like illness may be better designated as ACT-syndrome instead of drug resistant malaria

5.4 CONCLUSION AND RECOMMENDATIONS

Detection in parasite population circulating in Lagos of more and newer mutations previously unreported calls for more vigilance because this scenario could threaten the effectiveness of currently used antimalarial drugs and compromise malaria case management.

There is need therefore to make more investment in current and more sensitive molecular tools to enrich the quality of data derived from antimalarial resistance monitoring to enhance our malarial control efforts. The result of this study is a wakeup call to strengthen regulatory practices that would ensure stricter control of antimalarial use.

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