Table of Contents
Credits
Host: Sara Dong
Guests: Sumanth Cherukumilli, Milagritos Tapia, Adam Mamby Keita
Writing: Sumanth Cherukumilli
Edited and Produced by Sara Dong with support from the Infectious Diseases Society of America (IDSA)
Our Guests
Sumanth Cherukumilli, MD
Dr. Sumanth Cherukumilli is a third year pediatric infectious diseases fellow at the University of Maryland. He works with Drs. Milagritos Tapia, Karen Kotloff, Samba Sow, and Adama Mamby Keita on childhood antimicrobial resistance in West Africa. He was the winner of the 2024 Pediatric Infectious Diseases Society Sanofi Pasteur Fellowship award, which he used to launch a new neonatal sepsis study designed to study the impact of antibiotic choice on patient survival.
Adama Mamby Keita, MD, MSc
Dr. Adama Mamby Keita is the head of the department of epidemiology at the Center for Vaccine Development Mali in Bamako, Mali. He has spent over two decades conducting field research in Mali and has played critical roles in multiple surveillance studies, , and clinical trials (Phase II to phase IV). Dr. Keita has played a key role in data to action implementation in Mali and has been instrumental in saving the lives of many Malian children through his efforts.
https://www.researchgate.net/profile/Adama-Keita?ev=hdr_xprf
Milagritos Tapia, MD
Dr. Milagritos Tapia is a professor of pediatrics and a pediatric infectious diseases attending physician at the University of Maryland. She has served as PI or co-PI in multiple large vaccine-based surveillance studies and clinical trials and has played an extremely important role in introducing multiple vaccinations, including the Hib, pneumococcal, and meningococcal vaccines, in Mali, leading to a major decrease in the burden of vaccine preventable illnesses
Tapia, Milagritos | University of Maryland School of Medicine
Culture
Sumanth’s favorite author is Jhumpa Lahiri and he recommended The Lowland!
Mili shared her new standing desk
Adama likes outdoor activities like fishing
Consult Notes
Case Summary
18 month old male who presented with worsening respiratory distress and membranous pharyngitis
Key Points
Sumanth and Adama shared the differential diagnosis for this patient and compared how this may be impacted in resource limited settings.
- Sumanth shared causes of membranous pharyngitis in the context of the United States, including EBV and Arcanobacterium haemolyticum in particular. He also linked to items that he considers with severe illness and respiratory distress such as bronchiolitis, croup, epiglottitis, pneumonia, or sepsis.
- Adama then expanded on this differential in context of resource limited settings. He added earlier consideration of diphtheria, Hib epiglottitis, severe pneumococcal pneumonia and others.
- All of our guests discussed the constrains of management of severe respiratory disease in resource-limited settings, specifically the lack of mechanical ventilation.
The focus of this episode was diphtheria! Here is an introduction to the microbiology/epidemiology basics!
- Diphtheria is caused by toxigenic strains of Corynebacterium diphtheriae (or less commonly, toxigenic strains of other Corynebacterium spp such as C. ulcerans, and rarely, Corynebacterium pseudotuberculosis)
- Corynebacterium is an irregularly staining, Gram-positive pleomorphic bacilli
- Grows best on a medium containing sheep’s blood and fosfomycin or on Tindale medium (tellurite medium with cystine)
- Toxigenic strains produce an exotoxin that consists of an active A domain and a binding B domain, which promotes the entry of A into the cell
- Humans are the sole reservoir of C. diphtheriae
- Infection is spread by respiratory tract droplets and by contact with skin lesion discharge
- Check out the Red Book on Diphtheria (https://doi.org/10.1542/9781610027373-S3_004_002)
Clinical manifestations of diphtheria
Infection with C.diphtheriae typically presents as respiratory or cutaneous disease, but other manifestations can occur. Nontoxigenic strains of C. diphtheriae can cause sore throat and rarely other types of invasive infections. The incubation period is usually 2-5 days.
- Respiratory tract diphtheria usually presents as membranous nasopharyngitis, obstructive laryngotracheitis, or bloody nasal discharge. Symptoms typically begin 2-5 days after exposure. The clinical findings suggestive of respiratory diphtheria include adherent pharyngeal, palatal, or nasal membranes which are often gray and bleed with scraping — along with neck swelling, hoarseness, stridor, and/or serosanguinous nasal discharge
- Nasal diphtheria
- Typically occurs in infants
- Starts as cold/upper respiratory infection (URI) symptoms —> thick membrane develops
- Less lethal than other forms unless coexisting
- Tonsillar diphtheria
- Affects tonsils and pharynx; often coexists with nasal diphtheria
- Begins with 1-2 days of URI symptoms followed by development of pseudomembrane
- Membrane can expand and extend into larynx and trachea causing suffocation
- Extensive neck swelling with cervical lymphadenitis causing “bull’s neck” and obliterative edema is a sign of severe disease
- Laryngeal diphtheria: Typically a manifestation of facial diphtheria but occasionally a standalone illness
- Life-threatening complications include upper airway obstruction caused by membrane formation
- Nasal diphtheria
- Less commonly, diphtheria presents as cutaneous, vaginal, conjunctival, or otic infection
- A quick focus on cutaneous diphtheria:
- Begins as vesicles and pustules and progress to ulcers which may be covered by pseudomembrane
- Painful for 1-2 weeks, take 6-12 weeks to heal
- Important source of transmission, as organisms can be present in discharge for 2-6 weeks after infection
- More common in tropical areas and among urban unhoused
- Life-threatening complications include myocarditis with heart block and cranial and peripheral neuropathies
- Myocarditis:
- Begins between week 2 and 6; typically in week 2
- 10% of children develop; up to 2/3 of children with severe illness, almost universal with bull’s neck
- Can predict based on extent of pseudomembrane
- Delay in antitoxin administration results in increased risk
- 50% mortality rate
- Neuropathies:
- 2/3 of children with severe illness will develop
- Occurs 3-6 weeks after illness and can be motor, symmetric, and indistinguishable from GBS
- Myocarditis:
- A quick focus on cutaneous diphtheria:
- Case fatality rates are 5-10% with up to 50% in untreated patients
- For respiratory diphtheria, most untreated patients have infectious period from symptom onset and lasting for 2 wks (up to as long as 6 wks). Those treated with antibiotics are no longer infectious about ~5 days of antibiotics
- For cutaneous diphtheria, the clinical course can be subacute or chronic. Skin ulcers are likely no longer ifnectious within a week of initiating antibiotic therapy.
Sumanth discussed this paper at length during the episode
- Truelove, S. A., Keegan, L. T., Moss, W. J., Chaisson, L. H., Macher, E., Azman, A. S., & Lessler, J. (2020). Clinical and epidemiological aspects of diphtheria: a systematic review and pooled analysis. Clinical Infectious Diseases, 71(1), 89-97
- This was collection of systematic reviews that reviewed outbreaks over the past 100 years and determined the transmissibility of diphtheria, the case fatality rate, and other features of illness.
- Here is a nice overview from the paper (Figure 1) demonstrating the natural history of diphtheria with prevention and treatment interventions
Diagnosis and management of diphtheria
- Features that suggest a diphtheria diagnosis include:
- Presence of gray pseudomembrane (commonly bleeds with scraping)
- Appropriate epidemiologic risk factors (such as unknown or lack of vaccination history, outbreak setting, residence or travel to endemic area particularly within prior 10 days)
- Clinical manifestations consistent with respiratory disease: low grade fever, sore throat, malaise, cervical lymphadenopathy
- Clinical manifestations consistent with cutaneous diphtheria: shallow ulcers or chronic, nonhealing sores
- For lab diagnosis, specimens should be obtained from nares, throat, or any mucosal or cutaneous lesion
- *Remember to notify lab personnel if you suspect diphtheria
- Obtaining multiple samples increases yield
- Material should be obtained for culture from beneath the membrane (if present) or a portion of the membrane
- When possible, specimens should be collected prior to initiating therapy
- Clinical samples can be sent for both culture and PCR, if PCR is available —> The CDC Pertussis and Diphtheria Lab offers culture, toxigenicity testing, PCR, and serology
- When respiratory diphtheria is suspected, urgent empiric treatment with diphtheria antitoxin and antibiotics should be given promptly! Aggressive airway management is an important mainstay of management due to risk of obstruction
- Diphtheria antitoxin (DAT) is a hyperimmune antiserum produced in horses that binds and inactivates the diphtheria toxin
- Should be given as soon as possible based on mortality benefit and low rates of adverse events (prior to confirmation of toxin production, which can take several days)
- Antitoxin is most effective when given early because it can only neutralize toxin that has not yet entered cells
- Antibiotic therapy kills the organism, prevents further toxin production, and reduces transmission to others
- WHO guidance recommends: azithromycin, erythromycin, or penicillin
- Macrolide agents are generally preferred over penicillin given growing reports of penicillin resistance. Of the macrolides, azithromycin is preferred due to favorable side effect profile, ease of oral administration, and longer half-life
- As Sumanth discussed: Antitoxin reduces mortality but does not impact transmissibility. Antibiotics reduce transmissibility but do not impact mortality.
- Diphtheria antitoxin (DAT) is a hyperimmune antiserum produced in horses that binds and inactivates the diphtheria toxin
- Here are some WHO resources on diphtheria:
- World Health Organization. (2024). Clinical management of diphtheria: guideline, 2 February 2024.
- World Health Organization. (2024). Laboratory testing for diphtheria in outbreak settings: interim guidance, 26 January 2024. In Laboratory testing for diphtheria in outbreak settings: interim guidance, 26 January 2024.
- World Health Organization. (2021). WHO laboratory manual for the diagnosis of diphtheria and other related infections.
Adama discussed the challenges with resurgence of diphtheria and recent outbreaks reported in Africa
- Read more in this report on diphtheria outbreaks and guidance in WHO African Region
- He discussed the major challenge of vaccine coverage, particularly in Bamako, Mali where he works
- He mentioned this article looking at vaccine coverage and timeliness: Roose A, Onwuchekwa U, Tapia M, Sow S, Mast TC, Kotloff K. Assessing Vaccine Coverage and Timeliness in Bamako, Mali after the Introduction of Rotavirus Vaccine: A Modified Immunization Cluster Survey. Am J Trop Med Hyg. 2021 Oct 4;105(6):1594-1601. doi: 10.4269/ajtmh.21-0148. PMID: 34607307; PMCID: PMC8641340.
- Our guests also discussed the concept of the zero-dose child, defined as children who don’t receive a single dose of diphtheria, tetanus and pertussis-containing vaccine
- Here is an article on understanding immunization pathways in low and middle-income countries: Cata-Preta BO, Santos TM, Mengistu T, Hogan DR, Barros AJD, Victora CG. Zero-dose children and the immunisation cascade: Understanding immunisation pathways in low and middle-income countries. Vaccine. 2021 Jul 22;39(32):4564-4570. doi: 10.1016/j.vaccine.2021.02.072. Epub 2021 Mar 18. PMID: 33744046; PMCID: PMC8314014.
Infographics
Goal
Listeners will be able to identify the clinical manifestations, diagnosis, and treatment of diphtheria
Learning Objectives
After listening to this episode, listeners will be able to:
- Describe the spectrum of clinical manifestations of diphtheria, especially respiratory diphtheria
- Compare the importance of antitoxin and antibiotic therapy for management of diphtheria
- Identify the important of immunization for diphtheria
Disclosures
Our guests as well as Febrile podcast and hosts report no relevant financial disclosures
Citation
Cherukumilli S., Mamba, A.K., Tapia, M., Dong, S. “#120: Gray and Present Danger”. Febrile: A Cultured Podcast. https://player.captivate.fm/episode/a9b3641a-414d-493a-973f-42f131dfad5d/