Mycobacterium leprae transmission characteristics during the declining stages of leprosy incidence: A systematic review

Background Leprosy is an infectious disease caused by Mycobacterium leprae. As incidence begins to decline, the characteristics of new cases shifts away from those observed in highly endemic areas, revealing potentially important insights into possible ongoing sources of transmission. We aimed to investigate whether transmission is driven mainly by undiagnosed and untreated new leprosy cases in the community, or by incompletely treated or relapsing cases. Methodology/Principal findings A literature search of major electronic databases was conducted in January, 2020 with 134 articles retained out of a total 4318 records identified (PROSPERO ID: CRD42020178923). We presented quantitative data from leprosy case records with supporting evidence describing the decline in incidence across several contexts. BCG vaccination, active case finding, adherence to multidrug therapy and continued surveillance following treatment were the main strategies shared by countries who achieved a substantial reduction in incidence. From 3950 leprosy case records collected across 22 low endemic countries, 48.3% were suspected to be imported, originating from transmission outside of the country. Most cases were multibacillary (64.4%) and regularly confirmed through skin biopsy, with 122 cases of suspected relapse from previous leprosy treatment. Family history was reported in 18.7% of cases, while other suspected sources included travel to high endemic areas and direct contact with armadillos. None of the countries included in the analysis reported a distinct increase in leprosy incidence in recent years. Conclusions/Significance Together with socioeconomic improvement over time, several successful leprosy control programmes have been implemented in recent decades that led to a substantial decline in incidence. Most cases described in these contexts were multibacillary and numerous cases of suspected relapse were reported. Despite these observations, there was no indication that these cases led to a rise in new secondary cases, suggesting that they do not represent a large ongoing source of human-to-human transmission.

Our systematic review had specific research questions that did not include examining change in incidence over time or making future projections, but rather to describe the control measures implemented in each setting and use patient data to describe case characteristics. Trends of leprosy case detection were reflected in both the introduction (line 80) and discussion (line 975) with reference to Meima A, et al. (2004).

Reviewer #1: The primary conclusion of the study was that 'imported leprosy cases seem to have little impact on the endemic population, and they do not represent a large reservoir for ongoing transmission. This seems obvious from the start and no new analysis is included
We stated in the discussion (line 905) -'there is no evidence to suggest that an increase in foreign born leprosy cases arriving from high endemic areas contribute to a noticeable rise in local transmission.'. However, this was not a primary conclusion of the study. We also disagree that this is an obvious conclusion, especially given the high number of imported MB cases reported in a range of global settings, including Canada, Italy, Spain, New Zealand, Taiwan (Republic of China) and the United States. Moreover, migration patterns have changed considerably over recent decades, necessitating a new estimation of whether there is transmission by foreign born cases. Nevertheless, we have made it clearer in the methodology that demonstrating these types of associations was not an objective of the study (line 203).

In recent times the role of non-human reservoirs of M. leprae has gained notoriety in the literature. The importance of these reservoirs in sustaining leprosy is not yet confirmed. The authors do note that armadillos are associated with 64% of the cases in the United States. Does the persistence of leprosy in low endemic areas suggest there might be other non-human reservoirs, especially given the fact that imported cases do not seem to be contributing greatly to ongoing human-to-human transmission? In addition, recent literature suggests armadillos in South America also may be involved in zoonotic transmission. When one major source of infection comes under control, other lessor sources rise in importance. Does persistence of infection in low-endemic areas suggest sources other than human-to-human likely play a role?
We agree with the reviewer that we should elaborate on other sources that may sustain low level endemic transmission outside of those with a family history and other suspected sources detailed in the case records. This has now been added to the discussion (lines 942 -956), including comments on potential environmental reservoirs or zoonotic spread.
Regarding where a case may have acquired their infection, we agree with the reviewer. This cannot be established with absolute certainty. The definition of an imported case varied in our Date 21 April 2020 study, but the reason for classification as suspected non-autochthonous was usually described in the paper (e.g. the individual had recently immigrated from a high-endemic area). The difficulties in determining a patient's exact history were also highlighted in the discussion section (line 900) and we have further described this uncertainty (line 903).
Due to the nature of the individual case data sampled it was not possible to perform any meaningful time trend analyses or make projections for individual countries. Performing an analysis of pooled case data would also not be suitable given the broad range of different contexts and timeframes studied. Instead, the aim was to make a single assessment of the leprosy case characteristics over the specified period of incidence decline. We have stated this as a limitation (line 995).

Reviewer #2: The authors performed a systematic review for the literatures of leprosy and summarized the transmission characteristics of mycobacterium leprae during the low incidence of leprosy. The paper has public health implications because it provides different measures for prevention and control of leprosy.
Major comments:

4) Taiwan is an indispensable part of China and has never been a country. The author should revised current statement.
We thank the reviewer for their feedback. Please our responses to each point below: 1) We agree with the reviewer and this has been highlighted in the discussion (line 991).
2) We have cut down the text for the country descriptions and removed data overlapping with the quantitative results section.
3) We have created a full list of the 105 peer-reviewed studies used to leprosy extract case data. This can be found in Supporting Information 2 (S2) and contains author, title, country, date of publication and the number of cases collected. 4) We thank the reviewer for highlighting this and now refer to Taiwan (Republic of China) throughout the manuscript.

In the discussion the authors may emphasize the importance of access to health care and continued surveillance in rural areas for leprosy control. Although the data for urban vs rural cases were not available for all the reviewed low endemic countries, but countries like Iran, Morocco, Norway & Portugal showed the importance of surveillance in rural areas which for various reasons can harbor a more conducive environment for leprosy transmission than the urban areas.
We thank the reviewer for their feedback. M. lepromatosis has been added to the introduction as a cause of leprosy (line 64). For the countries included in this study, we have specified the 2019 new case numbers from latest WHO report where available. We agree with the reviewer's final point and have highlighted this in the discussion (line 1002).

Reviewer #1: Line 1008: incorrectly suggests that humans and armadillos share a single genotype of M. leprae
We agree with the reviewer and have changed this sentence (line 950) to: 'A zoonotic transmission pathway from exposure to armadillos has been proposed, with human patients from a previous study in southeastern United States shown to be infected with the same armadillo-associated M. leprae genotype.'

Line 1009: rather obscure citation. Should cite the original articles.
We have now cited the original article -Sharma, R., et al. 2015

Line 1043: should include distinguishing endemic/imported as a major limitation.
This has been added as a limitation (line 987). We thank the reviewer for their feedback. Please our responses to each point below: 1) We have added the publication date to the table in Supporting Information 2 (S2) for all 105 studies included in the quantitative analysis.
2) We have specified in the methodology section (line 166) that all countries or regions included had less than one new leprosy case detected per 100,000 population in the final year of the timeframe from which they were collected.
3) These details were described for autochthonous cases in the narrative descriptions where available. For example: • Canadian male who's only travel was to Florida and M. leprae isolate from his biopsy was identified as the armadillo-associated genotype 3I-2-v1.
• A rare case of documented patient-to-surgeon transmission of M. leprae in Germany.
• Male diagnosed with LL in the United Kingdom, returning after 40 years in the tropics. Two young adults who were contacts later found to have raised antibodies to M.
leprae and were subsequently given 6 months chemoprophylaxis with rifampicin Reviewer #3:

None
We thank the members of the PLOS Neglected Tropical Diseases (NTDs) editorial board and independent reviewers for taking the time to provide feedback. Please don't hesitate to contact us if you require any additional information. Sincerely,

Thomas Hambridge
PhD Candidate Erasmus MC, The Netherlands