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Atypical Clinical Manifestations of Loiasis and Their Relevance for Endemic Populations

Abstract Background Loiasis is mostly considered a relatively benign infection when compared with other filarial and parasitic diseases, with Calabar swellings and eyeworm being the most common signs. Yet, there are numerous reports in the literature of more serious sequelae. Establishing the relationship between infection and disease is a crucial first step toward estimating the burden of loiasis. Methods We conducted a systematic review of case reports containing 329 individuals and detailing clinical manifestations of loiasis with a focus on nonclassical, atypical presentations. Results Results indicate a high proportion (47%) of atypical presentations in the case reports identified, encompassing a wide range of cardiac, respiratory, gastrointestinal, renal, neurological, ophthalmological, and dermatological pathologies. Individuals with high microfilarial densities and residing in an endemic country were at greater risk of suffering from atypical manifestations. Conclusions Our findings have important implications for understanding the clinical spectrum of conditions associated with Loa loa infection, which extends well beyond the classical eyeworm and Calabar swellings. As case reports may overestimate the true rate of atypical manifestations in endemic populations, large-scale, longitudinal clinico-epidemiological studies will be required to refine our estimates and demonstrate causality between loiasis and the breadth of clinical manifestations reported. Even if the rates of atypical presentations were found to be lower, given that residents of loiasis-endemic areas are both numerous and the group most at risk of severe atypical manifestations, our conclusions support the recognition of loiasis as a significant public health burden across Central Africa.


Atypical Ocular Manifestations
From the 32 patients with atypical ocular symptoms, there was no report of co-infections with other agents causing ocular manifestations such as Onchocerca volvulus and/or Chlamydia trachomatis, nor were onchocerciasis or trachoma mentioned as possible causes of the manifestations observed. Supplementary Table 1 summarizes the information on ocular manifestations; the references are those in Section 1: Literature Review (Supplementary References).

Eosinophilia and Co-Infections
There were 199 cases with eosinophilia (defined as a peripheral eosinophil blood count >0.5 x 10 9 cells or a peripheral blood eosinophil count ≥6% [1]. Of these, 182 (91.5%) did not have co-infecting helminths reported, but malaria was recorded at the time of consultation in 5, amoebiasis in 4 (one of whom also had Trichuris trichiura, one had hookworm, and one had Strongyloides stercoralis), trypanosomiasis in 1 (who also had schistosomiasis) and tuberculosis in 1. Most infectious causes of peripheral blood eosinophilia are parasitic, and particularly helminth infection; protozoa, in general, do not cause eosinophilia [2]

Chi-Squared Test
Pearson's chi-squared test was used to test whether there was a statistically significant association between blood microfilarial density (MFD) levels and atypical presentation; where MFD levels had been categorised as: Zero (amicrofilaraemic, no mf detectable in blood smear), Low (greater than 0 but < 8,000 mf/ml) and High (≥ 8,000 mf/ml). All individuals for whom information on manifestation (either typical or atypical) and MFD were included. There are, therefore, more individuals included in this test than in the subsequent regression-based analyses, where data on a wider range of factors, specifically an individual's age, sex, residency status and MFD level (and eosinophilia status for Model 2) were required for them to be included.

MFD Levels Manifestations
Zero Low High Total  Typical  62  30  3  95  Atypical  40  21  16  77  Total  102  51  19  172 Pearson's chi-squared test using these data gave a chi-squared value of 13.492, which, with 2 degrees of freedom, yielded a p-value of 0.001176.

Model 2: Atypical Presentation ~ Age + Sex + Residency Status + MFD Level + Eosinophilia Status (n = 114 individuals)
We defined two multivariate logistic regression models (Model 1 and Model 2, the results of which are detailed in Figure 3 of the main text) that were fitted to the IPD collated through the systematic literature review. For both models, age was included as a continuous variable. Sex was defined as a categorical variable, with a reference of 0 for women and 1 for men. Residency status was included as a categorical variable; in almost all instances, residency status could easily be determined from the article text, but in a small number of cases (n = 3 individuals), it was impossible to ascertain whether an individual was living abroad or in an endemic country at the time of the consultation detailed in the reference, and thus that individual was excluded from the analyses presented here. MFD levels were included as a categorical variable, with an individual's MFD being either "Zero", "Low" or "High" (as defined in the section above). Eosinophilia status was also included as a categorical variable, with a reference value of 0 if the individual was not eosinophilic, and a value of 1 if the patient presented with eosinophilia (with being eosinophilic defined as having a peripheral eosinophil blood count > 0.5 x 10 9 cells or a peripheral blood eosinophil count ≥ 6% as described in the main text). The number of individuals in each category for the categorical variables is detailed in Supplementary Table 3. In addition to Models 1 and 2, we also explored a second set of models, defined here as Models 3 and 4. Although Models 3 and 4 share the same structure as Models 1 and 2, they differ in their categorisation of MFD levels. Instead of three categories (Zero, Low and High), individuals were assigned to one of four categories based on the MFD recorded. These categories were: Zero (amicrofilaraemic, no mf detectable in blood smear), Low (> 0 but < 8,000 mf/ml), High (≥ 8,000 but < 30,000 mf/ml) or Very High (≥ 30,000 mf/ml). The categorisations were chosen based upon their relationship with the risk of marked or severe adverse events (SAEs) following ivermectin treatment, with ≥ 8,000 mf/ml and ≥ 30,000 mf/ml associated, respectively, with an increased risk of marked adverse events (reversible functional impairment for several days), and permanent neurological sequelae including fatal encephalopathy [4].

Supplementary
Analysis of these models revealed similar results to those of the models presented in the main text, although the additional granularity granted through subdivision of the MFD categories allowed resolution of a potential dose-response relationship between MFD levels and the odds of presenting atypically.  Table 4), leading to substantial uncertainty in these estimates. Nevertheless, these results support the possibility of a dose-response relationship between atypical presentation and the intensity of microfilarial infection an individual harbours. The number of individuals in each category for the categorical variables considered in the analyses is provided in Supplementary Table 4 and the results of the models in Supplementary Table 5.

Supplementary Table 5: Results from Multivariate Logistic Regression Models 3 and 4.
Individuals are categorised into one of four categories based on their MFD levels; either Zero (amicrofilaraemic, no mf detected in blood smear), Low (> 0 but < 8,000 mf/ml blood), High (≥ 8,000 but < 30,000 mf/ml blood) or Very High (≥ 30,000 mf/ml blood).

Confidence Interval Calculation: Non-Parametric Bootstrap
In order to calculate the 95% confidence intervals (CIs) for the mean MFD of each residency status group shown in Figure 4 of the main text), an ordinary non-parametric re-sampling technique [5] was used. This process involved the following steps: 1. For each residency status group of size n, resampling (at random) with replacement of n patient MFD was conducted. 2. The mean of this newly generated sample was calculated. 3. Steps 1 and 2 were repeated 10,000 times to yield an empirical sampling distribution of the mean MFD for each different residency status group.