Hi everyone.

Welcome to Febrile, a cultured podcast about all things infectious disease.

We use consult questions to dive into ID clinical reasoning, diagnostics and antimicrobial management.

I'm Sara Dong, your host and a Med-Peds ID doc.

In today's episode, we're continuing to talk a little bit more about vaccine preventable illnesses.

If you haven't already, check out our last episode with Dr.

Adam Ratner.

You can also check out episode number 102 called Rubeola Response.

I will go ahead and introduce our guests today.

First up, we have Dr.

Sumanth Cherukumilli, who was previously on Febrile in episode number 95, which was live from Memphis and the St.

Jude PIDS Pediatric ID conference.

He is a 3rd year pediatric ID fellow at the University of Maryland.

He works with Drs.

Milli Tapia, Karen Kotloff, Samba Sow, and Adama Mamby Keita on childhood antimicrobial resistance in West Africa.

He was the winner of the 2024 Pediatric ID Society, PIDS, 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.

Hi, I am Sumanth.

I'm a third year Peds ID fellow at the University of Maryland.

Thanks for having me on, Sara, it's good to see you again.

He is joined by two of his mentors I just mentioned.

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, sero survey studies, and clinical trials from phase two to phase four.

He 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.

Hi everyone.

My name is Adama Keita.

I am, uh, a medical doctor from CVD-Mali working in clinical research, uh, to save lives.

Thank you.

Nice to meet you.

And last we have Dr.

Milagritos Tapia or Millie Tapia.

She's a professor of pediatrics and a pediatric ID attending at the University of Maryland.

She has served as PI or co-PI on multiple large vaccine based surveillance studies and clinical trials, and she has also played an extremely important role in introducing multiple vaccinations, including Hib, pneumococcal, and meningococcal vaccines in Mali, leading to a major decrease in the burden of vaccine preventable illnesses.

Hi, I am Mili Tapia.

I'm at the University of Maryland School of Medicine at the Center for Vaccine Development and Global Health.

And, happy to be here.

Uh, nice to meet you and look forward to a great conversation.

So Febrile is everyone's favorite cultured podcast.

So we ask our guests to share a little piece of culture, just something that makes you happy or that you've enjoyed recently.

I really like reading, and I like writing.

Um, so my favorite author is Jhumpa Lahiri.

And my favorite book is The Lowland and I try to plug that book to everyone I meet.

Um, if anyone has a chance , I would highly recommend reading it.

I recently, uh, reset up my home office and have a standing desk, and I, um, now have this other wall behind me, which of course your audience won't be able to see.

But, um, so I, I have to decide whether or not I want those things to show up on, on video conferences.

But, um, the standing desk is good, although I think I'm leaning on it right now.

I'm joined the, the 2020s.

Excellent.

And rounding us out, Adama, how about you?

Yeah.

Um, I, I really like outdoor activities, outdoor fishing and, uh, hunting.

Uh, people usually call me the man with two guns, one to kill pathogen, save life in in the city, and the second one to control some animal in the bush.

So I really like that.

Thank you.

Alright, um, well I'm gonna tell you guys a little bit about a case and get your thoughts.

So today we have an 18 month old male who presents with worsening respiratory distress after approximately three days of illness.

The symptoms were initially mild with minor rhinorrhea, but have progressively worsened, and the patient is having rapidly worsening difficulty in breathing over the past 48 hours.

The mother initially presented to a community hospital and was hospitalized, and later that patient was transported to a tertiary care center.

The patient is otherwise healthy, has never had similar episodes to this, has no history of prior hospitalization, atopy, or a family history of asthma or other medical conditions.

The patient lives in the city, has no contact with animals, but is unvaccinated and drinks unpasteurized milk.

There are no known sick contacts.

There's no family history of recurrent infections or autoimmune disease, and no additional family members, uh, attend daycare.

On physical exam, the child has an O2 saturation of 88% on supplemental oxygen.

He is tachycardic to 168 beats per minute and tachycardic to 75 breaths per minute.

He is afebrile.

Pertinent physical exam findings include a markedly exhausted appearance.

He does respond to the physical exam by crying and is moving all extremities appropriately, but otherwise is, you know, diminished and uninterested, and not really interacting with folks around him.

He has significant respiratory distress with tachypnea, head bobbing, nasal flaring, tracheal tugging, as well as intercostal and subcostal retractions.

He has audible stridor at rest.

His lungs are clear on auscultation and coating his nares is a thick gray nasal discharge, which appears to be adherent to the mucus membrane.

He has bilateral tonsillar hypertrophy with a thick gray layer extending over the bilateral tonsils and adherent to surrounding structures.

And so all of this is also associated with some bilateral cervical lymph adenopathy.

All right, so you guys get a lot of information.

What do you think is going on at the moment?

The first and most important thing always to do is to make an anatomic diagnosis, and it looks like this patient has a membranous pharyngitis.

So, I think that with a case like this, it's important to kind of break your differential diagnosis down by setting.

I think you would be thinking about different things based on where you are in the world.

So if you are in the United States, the most likely cause of membranous pharyngitis in a high income country, especially in people who are vaccinated, is going to be EBV, um, sometimes Arcanobacterium hemolyticum can also cause, uh, a membranous pharyngitis like picture.

But given that this child is unvaccinated, even if you were in a high income setting, you would definitely think about something like diptheria, which is kind of the classic cause of a membranous pharyngitis.

Um, and, you know, taking a step back, this patient is very, very sick.

Really critically ill.

So before you do this throat exam and find these kind of like very particular findings, you also need to consider other causes of really significant respiratory distress or severe respiratory distress, especially in the context of the stridor.

Um, and in that case you might be thinking about croup.

Obviously this is a very severe presentation for something like croup, which would make you think about like a community acquired bacterial tracheitis, which as most people are aware, is caused by Staph aureus.

You would al also think about something like epiglottitis, um, which in the United States is more likely to be caused by a nontypeable H flu, um, or another organism.

But, you know, outside the US where vaccination coverage is still low, Hib would still be what you would be thinking about there.

And then obviously you'd be thinking about pneumonia, severe viral infections that could be causing respiratory distress.

Obviously, they don't perfectly fit with the picture and given the degree of illness here, the fact that the patient is minimally responsive, you might be thinking about a systemic bacterial infection of some kind, may be associated with the localized picture, um, uh, a sepsis or a meningitis type picture.

I think that those are the things to really consider in a patient like this, but primarily with your physical exam, you're thinking about causes of membranous pharyngitis, and I'll turn it over to Adama to, to kind of talk about how we might approach a patient like this in a resource limited setting.

Thank you so much.

Thank you.

I think I will not repeat all you said, taking into, into account the clinical, uh, aspects that has been presented.

So in uh, the resource constrained setting, uh, people might think first about a severe respiratory infection, or, uh, something like a foreign body in the upper respiratory, uh, level or tonsillitis, throat infection, angina.

So that's the first thing we might think of.

But with the presence of, uh, a pseudomembrane, which is thick, and adherent, that is something not very common in the past year, but we might think about diphtheria with this outbreak in our area in West Africa.

So that's something to think about.

So it's very difficult in the resource, uh, constrained setting to have a clear diagnosis at first glance because of the limited test available, diagnostic test to have a, a clear diagnosis as compared to the developed world.

Yeah.

Those are all very good points.

Adama, I think another really difficult aspect of managing cases like this in resource limited settings is going to be the fact that oftentimes even in referral hospitals and national reference centers, it's very hard to find mechanical ventilators.

So patients who have severe respiratory distress, no matter what the cause, it can be very difficult to appropriately treat these patients.

And at this point, I think it's important to reveal that this patient was actually seen in a resource limited setting, in West Africa, and part of the reason why he was clearly hypoxic and had severe stridor, um, but wasn't intubated is because there wasn't mechanical ventilation available.

In the United States or in a resource rich setting, people always think about kind of croup versus bronchiolitis.

It's really bad when you have stridor, which is indicative of an upper airway obstruction of some kind, in this case, probably related to the pseudo membrane of the patient, and you have hypoxia because that means that your airway is literally constricting.

Mm-hmm.

Um, and that is usually an indication for intubation and mechanical ventilation, um, in a resource rich setting, but in a setting, in West Africa, since those resources are not available, oftentimes the best you can do is just oxygen.

Yeah.

I think one more thing to add is the training.

Even if the ventilator is available, people are not trained how to use this properly and to make a good surveillance of the patient that will be put on on ventilation.

So, beside that, the training on how to, uh, make a good intubation.

Yeah.

So to clear the airway, uh, is not also something that is right on hand in our context.

I would also add that, Adama, to add to what you just, um, said, an additional aspect to take into account is a monitoring that ventilation requires.

And, to take it a step further, even if you have the machine and even if you have absolutely trained to do the intubation, and which in this case is very, of course, medically complex in any setting.

Mm-hmm.

Um.

Uh, to be able to monitor a patient who is on ventilation, you need for capacity, for example, to do arterial blood gas measurements, which are not possible routinely, whether it's from lack of equipment or lack of reagents for the use of any available equipment.

So those are additional limitations.

So with that, we can talk a little bit about what our thought process was and has been during cases like this.

So we talked about EBV being a potential cause.

Membranous pharyngitis is a relatively rare manifestation of EBV.

So if you see multiple cases of membranous pharyngitis in an unvaccinated population, especially in a resource limited setting, it's not likely to all be related to EBV.

It's much more likely to be related to diphtheria, especially if you have confirmatory diagnostic testing for at least a few of those cases.

And that's kind of what you know happened here.

This patient was not formally diagnosed with diphtheria, uh, with lab testing, but given that there were multiple cases that happened around the same time in the context of a West African outbreak, the clinical diagnosis that was given to this patient was diphtheria.

And with that, I think it's important to discuss some of the features of diphtheria, some of the things to look out for with diphtheria, some of the clinical manifestations .

Um, and for that I will turn over to Dr.

Tapia.

All right.

So diphtheria is caused by one of three Corynebacterium.

That's Corynebacterium diptheriae, ulcerans, or, pseudotuberculosis.

On gram stain you have a gram-positive pleomorphic rods that stain irregularly.

They grow best on media containing sheep's blood and fosfomycin, or on, uh, Tindale medium, which is tellurite medium with cysteine.

Only the strains containing the beta pro phage or related phages are toxigenic, and it's the expression of the toxin, um, is based on the nutritional environment.

The toxin is composed of two subunits, an A and B sub unit, and it's the B sub unit that allows for entry in the A subunit, which exerts its toxic effect through inhibition of protein synthesis in the host cell.

The toxin is highly expressed in the absence of iron and, the phage mediates production of toxin and can be transferred in vitro and in vivo.

There are a number of clinical manifestations.

One is nasal diphtheria, which occurs primarily in infants.

And it begins as a cold and a thick membrane that develops.

This is the less lethal form of the disease.

There is tonsillar diptheria where it obviously affects the tonsils and pharynx, which can coexist with nasal diphtheria.

It begins with one to two days of URI symptoms, followed by a pseudo membrane.

The membrane can expand and extend into the larynx and trachea causing suffocation.

Cervical lymphadenopathy is present and causes a bulls neck or obliterative edema.

And this is the presentation that we're discussing here in the patient that we saw.

There is also laryngeal diphtheria and cutaneous diphtheria and other manifestations include conjunctivitis, otitis media, and septic arthritis.

It's important to note that there can be toxic complications of diphtheria.

So in addition to these presentations, which can be very acute and life-threatening.

There can be additionally life-threatening complications, including myocarditis.

That can begin, uh, week between two and six.

Typically week two.

Um, this can occur in 10% of children and up to a two-thirds of them can present with severe illness.

The occurrence of this complication can be predicted based on the extent of the pseudo membrane, and a delay in antitoxin administration usually increases the risk of this complication, and unfortunately there is a 50% mortality rate.

There can also be neuropathies.

Um, two out of three children with severe illness develop these and they occur typically three to six weeks after illness and can be motor, symmetric and indistinguishable from Guillain Barre syndrome.

It's a pretty complex presentation sometimes and again can be very, very serious and life threatening.

Yeah.

So, it's important to, to discuss what we know about diphtheria now.

Diphtheria was kind of an illness which was declining internationally.

There used to be millions of cases in the 1980s, but we've seen a resurgence of diptheria primarily in regions that are war torn.

Initially, like in Bangladesh, there was a huge outbreak in the late 2010s among the Rohingya, which were refugees from Myanmar.

Then there was an outbreak in Yemen, and now currently there's an outbreak in West Africa.

The latter outbreak is most likely related to declining vaccination coverage in the context of COVID-19.

Um, but because a lot of previous outbreaks were in eras when we had less data, there was a paper, uh, that came out in 2020.

Written by Sean Truelove.

They attempted to look at outbreaks over the last 100 years to put together some of the major features of the illness.

So they looked at like 7,000 articles.

Ended up including about 800 articles, which spanned outbreaks over the last 100 years and determined the transmissibility of diphtheria, the case fatality rate overall, and multiple other features of the illness, which are important to note in an era when we see increasing transmission of the disease.

What they determined is that the case fatality rate of diptheria is about 29% overall.

Kids who are older are less likely to die.

Kids who are vaccinated obviously are less likely to die.

And those treated with antitoxin are significantly less likely to die.

So the odds of someone dying after being given antitoxin is 0.24 in contrast to people who are not given antitoxin.

The best way to protect yourself from diphtheria, obviously, is to have universal vaccine coverage.

Having three doses of vaccination is 87% protective against illness.

It's not 100% protective against illness.

Unfortunately, developing natural infection does not confer immunity against diptheria.

The typical schedule for diptheria vaccine is obviously the DTaP vaccine.

So it's at two months, four months, six months, 15 to 18 months, and one dose at four to six years.

Children can get the vaccine afterwards, especially in the context of an outbreak, the problem if you're greater than seven years old is if you get either Tdap or the Td containing vaccine.

The amount of diphtheria antigen present in that vaccine is actually significantly lower than what's present in the DTaP vaccine.

So the protective efficacy of that version of vaccine is not well described as opposed to the DTaP vaccine.

As far as management of diptheria, there are two things that are critical.

One is antitoxin, which reduces mortality by about 76%.

And the second thing is antibiotics.

Antibiotics reduce transmissibility.

Antitoxin reduces mortality.

The two are mutually exclusive.

Antibiotics do not impact mortality.

Antitoxin does not impact transmissibility, so the problem is in most cases where diptheria is still present antitoxin is not widely available, which leads to very, very high mortality rates.

The other issue is that we, we have seen increasing resistance to penicillin, which was one of the first line treatments for diptheria to reduce transmissibility, making macrolides kind of the first line treatment.

But macrolides, in some places where diptheria is present may not be as widely available as penicillin and may not be guaranteed by the government making it difficult to control transmission.

The other thing is that infection control practices are, are, are difficult to enforce, especially in resource limited settings.

So if kids are in an open unit.

You can't really enforce droplet transmission precautions, and that kind of makes it easy for the disease to spread even in the hospital setting.

Now, the main points of diagnosis.

So there are two things that you need to be able to do, especially in the context of a small number of cases.

In an outbreak, it's a little different.

But when you have a small number of cases, if for instance, someone presents to the hospital and you think that they have diptheria in the context of the United States, you need to be able to isolate the organism.

So you take a swab and you want to get either on the tonsils or around the pseudo membrane, and then send that swab for culture and actually grow it.

And then demonstrate phenotypic toxin production through something called the Elek Test.

Now, the problem is that the Elek test requires antitoxin as one of its reagents.

If you don't have antitoxin, which is the case in many resource limited settings, it can be very difficult, um, to actually perform the Elek test.

So you have no evidence of phenotypic toxin production in that setting.

Also, if you don't have great microbiologic capacity in your country, it can also be difficult to culture the organism.

And keep in mind that many of these patients get pretreated.

So if they're very sick at the time of presentation to another hospital, then they may get antibiotics as soon as they show up.

So their culture will be sterile by the time that they present to a hospital where the test is actually performed.

So another way that you can make the diagnosis theoretically, is through the use of PCR.

The problem with PCR is that you can get what looks like a toxigenic Corynebacterium diphtheriae, but the presence of the toxigenic gene doesn't actually mean that the toxin is expressed phenotypically.

So Elek testing actually tells you whether or not the isolate is phenotypically producing toxin, but PCR can give you an idea of whether or not toxin is present in the isolate, doesn't tell you whether or not it's actually expressed.

So it's kind of challenging.

You need to demonstrate phenotypic toxin production, but if you don't have the ability to culture, you can't do that, so sometimes PCR is all you have.

And only toxigenic diptheria can produce the manifestations that we're talking about.

Non toxigenic Cornyebacterium diphtheriae can produce other things like myocarditis, conjunctivitis, the things that we were discussing, especially in immunocompromised patients, but only toxigenic diphtheria can produce this aggressive tonsillar disease that we're talking about.

So in the context of just a few cases, culture is vital.

But in the context of an outbreak, you either have to use PCR knowing that it's an imperfect surrogate for culture, or you have to make the clinical diagnosis.

In Mali, oftentimes the clinical diagnosis is all we have.

Most of our patients were pretreated with antibiotics, and about 52 patients were ultimately tested, but only one or two had positive cultures.

Whereas when we use PCR, we find we found higher positivity rates.

So that is kind of like a primer on the diagnosis of diptheria.

It would be good to talk a little bit about antitoxin, and its restricted availability in the region.

And I, I think Adama maybe if, if you could talk about that.

Yeah, it's very sad.

It's very heartbreaking hearing that 76% would have been saved if antitoxin, uh, were available.

So that's something that, uh, uh.

Is, uh, making me very, very sad.

You know, over 50 suspected cases that have been identified in Malian Bamako here, at Gabriel Toure.

All of them unfortunately died.

So that's very, very sad because the anti-toxin is not available in the country.

The only thing that we were able to implement is, uh, the vaccination around, uh, each suspected case, but the case themself, we were not able to save them with something that is available elsewhere.

So that's really, uh, a big challenge.

So, we also mentioned some of the challenge, that's the vaccine coverage.

Recently, Anna Roose and a team in Mali here.

They publish on vaccine coverage after rotavirus vaccine introduction in our national immunization.

So the vaccination coverage is really low, below what is expected to be the acceptable one.

So it was around 86% vaccine coverage.

So with the Covid pandemic and vaccine hesitancy, public unrest within the country, within the region, all these contribute to this decreased vaccine coverage.

So making more vulnerable people, uh, and children, subject to this preventable disease.

I wonder if, do you guys think it would be helpful to talk about management of household contacts?

Like Adama when with these patients, caretakers, relatives, other members, did you provide antibiotics to those?

Is that something that was considered.

Yeah, absolutely.

It's really important to prevent the spread of the disease by preventive antibiotics and vaccination of the close contact.

So this patient, the route from their home to the health facility, the final endpoint, is really sometime long.

They pass by several parts.

Some are seen by traditional healers.

Some go to, uh, CSComs (Centres de Santé Communauté) level.

CSComs is the first level of the overall health system, so there are a lot of contact to be monitored, to be treat.

So looking at the resource that is need for that and the, movement of the, the people in the country, it's really difficult.

It's really very challenging to get hand on all the potential contact and prevent the spread of the illness.

This approach is used for some of the suspected case administration of antibiotic and vaccination, but it's not done for all, unfortunately.

Yeah, And just to piggyback off of that, um, the Red Book actually has recommendations on how to manage, uh, diptheria and diptheria exposure.

First of all, the, the, the primary thing that you need to do.

This is why cultures are so important.

You need to document elimination of toxigenic strains.

Um, so you need two consecutive negative cultures, taken 24 hours apart after therapy.

You also need to assess everyone in the household and close contacts, to see if they're carriers of toxigenic strains.

All close contacts should also receive antimicrobial prophylaxis with either oral erythromycin or penicillin.

Um, and if they're carriers, then they need to be treated.

Those patients who are carriers need to be treated for 10 to 14 days with oral erythromycin or, or azithromycin for five days, or one dose of IM penicillin.

Now that's what the Red Book says.

Given that globally there are increasing resistance rates to penicillin.

The WHO recommends macrolide antibiotics for diptheria period over penicillin.

Um, if you are a carrier, just like someone who has been treated, you need two consecutive negative cultures.

If you're still positive, you need an additional 10 days of oral erythromycin.

All patients need to be on droplet precautions until they've completed therapy and they're culture negative.

And then all close contacts, in addition to being tested for active surveillance and getting antibiotic prophylaxis to, you need to have seven days of active surveillance.

Everyone who's a close contact needs to receive a dose of DTaP, T dap or Td.

So just, um, some things to keep in mind, uh, with regards to people who are, um, exposed to the disease, especially in a high resource setting.

Now, I think we've also discussed the West Africa outbreak a lot.

And I think it's important to put some numbers around it.

We've had around 40,000 cases of diptheria throughout the West African region.

The outbreak, I think, began in Mauritania.

And then spread to regional countries.

Um, there's probably significant undercounting the number of cases because most of this number is based on cases that are actually confirmed.

Um, so as we discussed, it can be very hard to confirm a case of diptheria in a resource limited setting.

Um, and we don't have great ideas of what the mortality rate is, but.

You know, at least in a place like Mali, while we don't have the same numbers as in places like Nigeria, the mortality rate for confirmed cases has been very, very high because of the lack of antitoxin.

I'll take another opportunity to ask Adama about unvaccinated children, period.

So the reasons for unvaccinated children in the United States are different from unvaccinated children in a country like Mali.

And I think that, you know, it is very uncommon to actually have unvaccinated children in Bamako, whereas it is much more common in rural areas.

And I think what, um, Adama brought up is that the route that a baby takes to get to us in Bamako can be long.

And he brought that up, but I don't know that he actually highlighted the fact that many of the cases that we saw in Bamako were actually from rural areas.

Yeah.

Um, and so maybe, um, Adama, if you could just talk a little bit more about zero vaccination, zero vaccinated babies.

And that's actually, I forget what the term is now, Sara, but there is a term now in public health looking at zero that the zero vaccine babies or something like that.

Mm-hmm.

There's a term in public health.

It's a zero dose targeting.

Zero, yeah.

Zero dose, thank you.

Zero dose.

Mm-hmm.

Yeah.

I think, uh, we have a lot of zero dose in in Bamako in a area where we found some suspected case of diphtheria in common six.

So, but as you mentioned, most of the case were coming from the rural area outside Bamako, and all of them did not have the diphtheria vaccine previously or have a s reported by the parents few, uh, doses.

So yeah, it's really important to have the zero dose number, the vulnera vulnerability of the children.

So yeah, there are some project now working on that.

I hope that will con to reduce the zero dose within our uh, region.

Usually people, uh, said in our culturally that you will not die before the day you set with God.

But, uh, we are seeing that people are dying before that day in our country and for something that is really preventable.

So I think we need to resolve basic medical need all around the world to have equity in access of, uh, basic medical needs.

Thank you.

Thanks to Sumanth, Adama and Millie for joining us today.

This is part of a series of vaccine preventable illness topics.

Don't forget to check out episode 1 0 2 called Rubeola Response, as well as our last episode of Febrile entitled Old Scourges, New Surges.

You can find more info on the website febrile podcast.com, where we have the Consult Notes, which are written supplements to the episodes with links to references, our library of ID infographics, and a link to our merch store.

Febrile is produced with support from the IDSA, Infectious Diseases Society of America.

Please reach out if you have any suggestions for future shows or want to be more involved with febrile.

Thanks for listening.

Stay safe and I'll see you next time.