Shining light on the dark matter of pertussis: evidence for an asymptomatic carriage state from a longitudinal cohort of mother/infant dyads
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eLife Assessment
This important study provides evidence for asymptomatic Bordetella pertussis carriage among mothers in a longitudinal cohort in Zambia, significantly advancing understanding of transmission dynamics. The evidence presented is convincing, with strengths including routine sampling irrespective of symptoms and rigorous qPCR methodology, although confirmatory diagnostics would further strengthen the claims. Overall, the study represents an influential contribution to the field of infectious disease epidemiology.
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Abstract
Pertussis remains an enigma partly due to the uncertain impact of asymptomatic cases on transmission. Contributing to this knowledge gap is a lack of high-quality disease surveillance, particularly in those low- and middle-income countries that experience high disease burdens. Here we present analyses based on our prospective longitudinal surveillance of a rolling cohort of 1,315 mothers and their newborn infants in Lusaka, Zambia across 2015 (8,704 unique study visits). We detail the timing, duration, and intensity of qPCR-based IS481 signals in individual subjects and within mother/infant dyads. We find that IS481 signal strength: A) in mothers predicts contemporaneous and future IS481 detections in infants, B) in infants predicts, to a lesser extent, detections in mothers, and C) predicts respiratory symptoms in infants but not mothers. We profile a subgroup of 50 infants and 54 mothers who displayed evidence of persistent colonization (median duration 8 weeks) wherein most mothers were entirely asymptomatic. We also include a critical assessment of qPCR test reliability across IS481 signal strengths. Our results indicate that pertussis transmission routinely occurs between minimally symptomatic mothers and their newborn infants, and demonstrate the routine occurrence of long-duration, mild and minimally symptomatic pertussis infections.
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eLife Assessment
This important study provides evidence for asymptomatic Bordetella pertussis carriage among mothers in a longitudinal cohort in Zambia, significantly advancing understanding of transmission dynamics. The evidence presented is convincing, with strengths including routine sampling irrespective of symptoms and rigorous qPCR methodology, although confirmatory diagnostics would further strengthen the claims. Overall, the study represents an influential contribution to the field of infectious disease epidemiology.
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Reviewer #1 (Public review):
Summary:
The study investigates the role of asymptomatic pertussis carriage in transmission between mothers and their infants, in particular. The authors used a longitudinal cohort study that involved 1,315 mother-infant dyads in Lusaka, Zambia, and they utilized qPCR-based detection of IS481 to track Bordetella pertussis transmission over time. Insights from the study suggest that minimally symptomatic or asymptomatic mothers may act as a reservoir for B. pertussis transmission in the infants, thus challenging the traditional surveillance methods that focus on symptomatic cases. Additionally, the study also identified a subgroup of persistently colonized individuals where mothers were majorly asymptomatic despite sustained bacterial presence.
The authors aimed to improve comprehension of pertussis …
Reviewer #1 (Public review):
Summary:
The study investigates the role of asymptomatic pertussis carriage in transmission between mothers and their infants, in particular. The authors used a longitudinal cohort study that involved 1,315 mother-infant dyads in Lusaka, Zambia, and they utilized qPCR-based detection of IS481 to track Bordetella pertussis transmission over time. Insights from the study suggest that minimally symptomatic or asymptomatic mothers may act as a reservoir for B. pertussis transmission in the infants, thus challenging the traditional surveillance methods that focus on symptomatic cases. Additionally, the study also identified a subgroup of persistently colonized individuals where mothers were majorly asymptomatic despite sustained bacterial presence.
The authors aimed to improve comprehension of pertussis transmission dynamics in high-burden low-resource settings, and they advocated for enhanced molecular surveillance strategies to capture full pertussis infection, including those that might have gone undetected.
Strengths:
The strengths are the use of innovative study design, especially the longitudinal approach and routine sampling, rather than symptom-driven testing that minimizes bias in the study. The methodology was also rigorous and transparent by evaluating the IS481 signal strength to classify pertussis detection and conducting retesting to assess qPCR reliability. There were also important epidemiological insights, and the findings challenge the traditional wisdom by suggesting that pertussis transmission may frequently occur outside of symptomatic cases. The findings also showed its relevance to global health and policy by arguing for the incorporation of molecular tools like qPCR for surveillance of pertussis in low-resource settings.
Weaknesses:
These include reliability on qPCR-based detection without additional validation measures like confirmatory culture or serology. There are also potential alternate explanations for transmission patterns observed in the study such as shared environmental exposure or household transmission. Additionally, there is limited generalizability as the study was done in a single urban site in Zambia. There is also a lack of functional immune data.
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Reviewer #2 (Public review):
Summary:
In this paper, the authors describe the results of a longitudinal study of pertussis infection in mother/infant dyads in Lusaka, Zambia. Unlike many past studies, the authors assessed the infection status of individuals independently of whether they were symptomatic for a respiratory infection. As a result, this work represents one of the first studies specifically designed to assess asymptomatic transmission of pertussis. Using qPCR, the authors find strong evidence for the role of asymptomatic transmission from mothers to infants and also evidence for long-term bacterial carriage. This work represents an important contribution to our understanding of the global burden of pertussis. Also, it highlights the still under-appreciated role of asymptomatic transmission across many infectious diseases …
Reviewer #2 (Public review):
Summary:
In this paper, the authors describe the results of a longitudinal study of pertussis infection in mother/infant dyads in Lusaka, Zambia. Unlike many past studies, the authors assessed the infection status of individuals independently of whether they were symptomatic for a respiratory infection. As a result, this work represents one of the first studies specifically designed to assess asymptomatic transmission of pertussis. Using qPCR, the authors find strong evidence for the role of asymptomatic transmission from mothers to infants and also evidence for long-term bacterial carriage. This work represents an important contribution to our understanding of the global burden of pertussis. Also, it highlights the still under-appreciated role of asymptomatic transmission across many infectious diseases (including vaccine-preventable ones).
Strengths:
Unlike many past studies, the authors assessed the infection status of individuals independently of whether they were symptomatic for a respiratory infection. As a result, this work represents one of the first studies specifically designed to assess asymptomatic transmission of pertussis. Using qPCR, the authors find strong evidence for the role of asymptomatic transmission from mothers to infants and also evidence for long-term bacterial carriage.
Weaknesses:
While I am quite enthusiastic about the work, I am concerned that a number of likely relevant confounders were not discussed and that the broader implications of their findings were not well grounded in the existing literature. For example, I could not find information on the vaccination status of the mothers in the study. Given the conclusions about asymptomatic transmission and the durability of immunity, it is important to know the vaccination status of the mothers. Moreover, did the authors have other metadata on the mother/infant dyads, e.g., household size, vaccination status of household members, etc.? Given the potential implications of more widespread asymptomatic transmission associated with pertussis infection, I believe the authors should better couch their results in the context of the broader debate around asymptomatic transmission.
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