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BMJ 2021; 372 doi: (Published 03 March 2021) Cite this as: BMJ 2021;372:n617
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COVID-19 vaccination – Don’t forget the lymphatics!

Dear Editor

The impact of recently-developed vaccines against COVID-19 is unarguably impressive. High levels of defence against infection and even higher levels of protection against severe disease have been achieved in an unprecedented time-frame. Such advances are a reminder of the power of the adaptive immune system. Whilst much discussion has been devoted to the relative roles of antibodies and T-cells, the relevance of the lymphatic system to effective immune responses has been largely forgotten. This is not surprising given that medical textbooks tend to skim over the role of lymphatics in facilitating vaccine-driven (and pathogen-driven) immune responses. Lymphatics are however a critical component in the pathway from vaccination to protection that should not be neglected.

The immune system does not develop in anatomical isolation. Its development is inherently linked to that of the lymphatic system. Furthermore, its function is synergistically linked to lymphatic activity. With on-going research, we are now slowly appreciating how important the lymphatic system is for generating and sustaining immune responses.

All COVID-19 vaccines in current use deliver their payload into muscles. The Pfizer-Bio-nTech and Moderna vaccines both use lipid nanoparticles (LNP) as mRNA carriers, whilst the Oxford Astra-Zeneca and Sputnik vaccines use adenovirus vectors. mRNA and viral vaccines must transfect cells to produce their corresponding proteins, whilst other vaccines, such as the Chinese Sinovac vaccine, deliver inactivated virus proteins directly into muscle. Whichever delivery system is used, viral proteins do not initiate immune memory responses in muscles. They must be transported to lymph nodes in order to initiate a response. This transport occurs primarily within antigen-presenting cells (APC), specifically dendritic cells (DC), which are drawn from blood into the vaccination site by local inflammation. Within tissues they are activated and endocytose and process viral proteins, expressing them in the context of surface major histocompatibility complex (MHC) molecules. The critical next step is entry into tissue-draining afferent lymphatics; this process is actively facilitated by expression of lymphatic-homing molecules on activated DC. Some antigen may also travel directly to draining lymph nodes. Even though this occurs by passive convection, it still relies on the presence of intact functioning lymphatics. Only once delivered to local lymph nodes can the antigen trigger a specific adaptive memory response from naïve B- and T-cells located there.

So, what then happens to those patients without a healthy, functioning lymphatic system? This is a non-trivial question as lymphoedema has a prevalence of around 1 in 1000 in the U.K. Such patients also tend to fall into high-risk groups for COVID-related complications, not least because lymphoedema is commonly secondary to treatment for cancers. Around 20% of patients with breast cancer develop lymphoedema after lymph node resection / radiotherapy. Furthermore, a significant number of patients suffer with a primary (developmental) lymphoedema syndrome, making up around 16% of patients attending lymphoedema specialist services. Whatever the cause, the resulting lymphatic dysfunction results in impaired immune responses to infection (commonly manifesting as persistent, often refractory cellulitis and viral warts). Areas of lymphatic swelling are immunologically vulnerable because damage to lymph vessels and pathways prevents trafficking of immune cells to lymph nodes. We surmise that cells such as lymphocytes become trapped within swollen tissues, rendering them unable to conduct vital immunological surveillance, whilst cells such as DC are rendered unable to deliver and present antigens to lymph node-resident lymphocytes.

This close relationship between lymphatics and the immune system raises important clinical questions regarding vaccination against COVID-19 for patients with lymphatic problems. Vaccination is most commonly administered into the deltoid muscle. Although no direct evidence is currently available, we suggest that patients with upper limb lymphoedema (such as those with previous lymphadenectomies secondary to breast cancer treatment) are likely to mount suboptimal systemic immune responses resulting in compromised immunological protection against COVID-19. The process of inoculation will also create a portal of entry for microorganisms within an already immunologically compromised site. This has the potential to result in a soft tissue infection of the lymphoedematous limb. We propose therefore that, where possible, inoculation should avoid areas of lymphoedematous swelling - an unaffected limb or buttock should be chosen instead.

We have recently produced a consensus document ( ) with the help of the patient’s charity the Lymphoedema Support Network (LSN), detailing advice regarding vaccination against COVID-19 for patients who suffer from lymphatic problems. This document will be useful for clinicians and allied healthcare professionals who administer the vaccine or advise patients regarding vaccination. Our main messages are, firstly, that vaccination is still advisable, and secondly, that the vaccine should not be given into a lymphoedematous limb where an alternative site, such as an unaffected limb or buttock, is available, even if this is not a manufacturer-recommended site for vaccination. If lymphoedema is widespread, the limb or buttock least-affected by lymphoedema should be chosen. Patients should be warned that an increase in local swelling may occur after vaccination, but this should resolve promptly.

In summary, the lymphatic system needs much more consideration in science if we are to understand our body’s immunity and response to infection better.

Competing interests: No competing interests

02 May 2021
Julian A C Pearce
Dermatology Registrar and Academic Clinical Fellow
Professor Peter Mortimer, Professor Sahar Mansour, Dr Kristiana Gordon, Professor Derek Macallan
St George's University Hospitals NHS Foundation Trust
St George's Hospital, Blackshaw Road, Tooting, London. SW17 0QT