Drs. Maria Gabriela Segura, Misti Ellsworth, and Michael Chang from UTHealth Houston McGovern Medical School and Children’s Memorial Hermann Hospital chat about an unusual pediatric case of fever of unknown origin.

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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 MedPeds ID doc.

Today, we are joined by a team from the University of Texas Health Science Center or UTHealth in Houston, McGovern Medical School and Children's Memorial Hermann Hospital.

First up, I'll introduce our host, Dr.

Maria Gabriela Segura.

She is a third year pediatric infectious diseases fellow at UTHealth Houston.

Hi, I go by Gaby and I'm very grateful for being here today and excited to record this episode with you.

She is joined by two discussants.

Dr.

Misti Ellsworth is an Associate Professor of Pediatrics and Director of Pediatric Infection Prevention.

Hi, I'm Misti Ellsworth, and I'm excited to be here today on the Febrile podcast.

We also have Dr.

Michael Chang, an Assistant Professor of Pediatrics and Co Director of the Pediatric Antimicrobial Stewardship Program.

Hi, I'm Michael Chang, and I'm also very excited to be here today.

So, before we jump into the case, we always ask our one question as everyone's favorite cultured podcast.

I like to ask the guests to share a little piece of culture, really just something non medical that makes you happy or that you enjoy doing.

So, Gaby, maybe I'll start with you.

Yes.

Yeah, we were talking about this a lot, really, like, outside of work, for me, I like to run.

I do like to watch a lot of Netflix and HBO shows.

The main thing is spending time with my kids.

I have two boys, a seven year old and a two year old.

We like to travel, mostly to beach destinations, and pretty much doing anything with my husband and my kids is my outside thing

Love it.

Love it.

What about you, Misty?

So, I was super excited this week that The Bear Season 3 came out on Hulu, so pumped about that.

And then I've been reading Agatha Christie novels because it's too hot to go outside.

Yeah, I have the new season of The Bear queued up, but hopefully I'll start some of them this weekend.

I'm excited.

And you, Michael, what do you have?

Yeah, so right before we started recording, we were talking about how I've been listening to so much K pop because my daughter's like a huge K pop fan, but my culture moment isn't actually about K pop.

So I, there's a band from London called The Last Dinner Party.

And I think that was like the first album I had listened to that wasn't K pop in like months.

It was such a breath of fresh air.

And I was like, Oh my God, I didn't even know I needed this.

And so I probably listened to that album twice a week, all the way through like every week since like January.

It's so good.

Yeah.

They're like a, kind of a rock theatrical group.

All women.

It's awesome.

So, uh, highly recommend if you've never heard of The Last Dinner Party, check them out.

I love it.

Um, well, I am going to hand it over to Gaby who's going to lead us through today.

It sounds like you had a case of fever of unknown origin.

Yes.

So, a usual month in service, I get a call from the pediatric team about a previously healthy 11 year old girl, she was admitted for the workup of fever of unknown origin.

In the middle of winter in the Texas Gulf Coast region, she started having fevers and decreased energy.

Mom says like she wouldn't get out of bed.

She was doing Tylenol as needed.

It improved the symptoms for a little bit and then she would again feel very tired and having non quantified temperatures, uh, fever.

On the second day, mom took her to an urgent care.

They did, they swapped her for strep throat, COVID, and flu.

Everything was negative.

So that same afternoon at home, she had a temperature that they quantified to 101 F.

They stayed at home with Tylenol as needed, but on the fourth day of illness, she's still not improving, so she went to PCP.

PCP diagnosed her with left otitis media and prescribed amoxicillin, which she was taking but didn't really improve at any point with it.

So on day five, mom again came to the ED, they did a UA, they did a rapid mono test, they got another group A strep test, COVID, and a chest x ray.

All of them were normal.

While she was on the ED, her temperature went up to 102.

7 F.

By now, about a week after the symptoms started, she's still having daily fevers, very tired, and now having a new onset non productive cough.

However, they explained that the cough would persist until she vomits, and so the mom, again, took her to the ED for assessment once this started.

So in the ED, her temperature was 102.7 F she was noted to be tachycardic and just looking ill, so she ended up being admitted for FUO workup.

They stopped the amoxicillin that she was still on because at this point they didn't see any physical exam findings that were consistent with acute otitis media.

They got a blood culture and a urine culture, and then she was brought up to the floor.

So for her past history, her birth history was unremarkable, no pertinent past medical history, no surgeries, and family history was also unremarkable.

Her immunizations were up to date.

She lives with mom, dad, and her sister, they don't have any pets, and she's not around any animals that she's aware.

Mom stays at home, dad works in carpet installations, they both go to school, both sisters.

There were no sick contacts or no other exposures in the history.

So, when we saw her the first time, her vital signs were unremarkable.

She was afebrile at that point and on room air.

And her, the rest of her physical exam, the only significant finding was rash that we thought it was consistent with keratosis pilaris on both upper arms.

And mom had said that it, she's had that in the past.

So we weren't sure if this was really like a worsening of the same rash or if it was just her baseline keratosis pilaris.

And then she didn't have any edema in upper extremities or no skin peeling.

Nothing in throat, ears, no lymph nodes were present at that time.

So, the initial labs that they collected, she, uh, had a mild anemia with a hemoglobin of 11.9, mild thrombocytopenia of 156.

Her inflammatory markers were a little high with a ESR of 23 mm/hr, a CRP of 36 mg/L, and procalcitonin of 0.4 ng/mL.

And her CMP had a mildly elevated AST to 111.

The primary team did a further workup of ANA, COVID IgG, group A strep PCR, a transplant respiratory viral panel, CMV antibodies, EBV panel, HIV and mycoplasma PCR, all of those were negative.

This is the case that we have.

So based on this presentation, Dr.

Ellsworth, what are you, what would be your differentials so far?

Okay, so to summarize, we have a 13 year old girl with fever for one week with fatigue, mild rash, cough and emesis with lab results showing a mild anemia, mild thrombocytopenia, some elevated inflammatory markers and LFTs.

And she's also been taking oral amoxicillin with really no improvement in her symptoms.

Overall, I'd say our symptoms are non specific, and, you know, it could really be caused by multiple different infections.

Uh, seasonality can often help when we're considering the differential diagnosis in these cases, and this was the winter in the Gulf Coast of the United States.

So since it's winter, of course, we're gonna think about all those viral etiologies, such as flu, RSV, parainfluenza, adeno[virus], all those things should be considered with her nonproductive cough.

Other viruses with similar symptoms include SARS CoV 2, and then of course there's other viral causes with nonspecific syndromes that we always think about like enterovirus and Epstein Barr virus.

For bacterial infections, you know, I would consider community acquired pneumonia or a group A streptococcal infection, but she's received oral amoxicillin without benefit, so makes those things maybe less likely.

Despite the cough with primarily nonspecific systemic symptoms, she could have a developing septic arthritis or osteomyelitis secondary to Staph aureus or Kingella.

However, Kingella is less likely given her age.

So urinary tract infections and urosepsis should be considered, but her testing was reported to be negative.

Uncommon, but meningococcal infections, and with the appropriate epidemiologic factors like travel, consider typhoid, leptospirosis, but both these would be rare.

At 11 years of age, it's also worthwhile to obtain a sexual history, consider infections such as disseminated gonococcal infection or syphilis.

Acute HIV could present with nonspecific symptoms as well.

Um, in our region, we also should always consider some vector borne illnesses.

So murine typhus is often missed because it has very nonspecific presentation, can have an uncomplicated clinical course, and the fact that only a small portion of patients recall a flea bite or exposure to infested animals.

Other nonspecific manifestations can include myalgias, malaise, nausea, vomiting, and abdominal pain with tenderness in more than half of the cases.

Bartonella henselae infection or cat scratch disease is also pretty high yield for your FUO diagnosis, with proper travel history, we might also consider ehrlichiosis or Rocky Mountain Spotted Fever.

So sometimes in our region, we do see things that are considered tropical illnesses, so we should put that on our differential too.

So things like Zika, dengue, and possibly malaria if we find the right risk factors or history.

There are numerous pediatric inflammatory conditions like Kawasaki disease, staphylococcal and streptococcal toxic shock syndrome, and macrophage activation syndromes that could also present with her symptoms.

Gaby, I think additional imaging and echocardiogram can help us.

Also, is there any additional history that might be helpful?

Yes.

So, for imaging, we have a chest x ray that was normal.

We had an echo done on the 11th day of illness.

This was read as normal too.

And then we got an abdominal ultrasound, of course, part of FUO workup as well, that showed non occlusive thrombus within the mid aorta.

There was some, uh, trace left pleural effusion, hepatomegaly with left kidney above the second standard deviation for her age.

So when we got this result, we got a aortic ultrasound that, again, showed previously seen hyperechoic filling defect in the upper abdominal aorta, seen again, causing non occlusive thrombosis.

They don't really specify the measures of the clot, they just said the proximal aortic diameter was 1.4cm and the mid aortic diameter is 1.0cm.

So with this result, we got a second echo once we found these aortic thrombus, and the repeat echo showed mild dilation of the proximal left main coronary artery with a normal sized mid portion of the left main coronary artery.

So, hematology was consulted and they recommended a workup that included protein C, protein S, anthrombin activities, lupus anticoagulant, beta 2 glycoprotein, cardiolipin, and factor 5 Leiden.

All of those were normal.

So what do you think we should have in consideration with this information as a differential diagnosis?

So, the normal chest radiograph doesn't exclude but does make community acquired pneumonia less likely, especially with the later onset of her cough.

A viral or respiratory tract infection also seems less likely.

With the ultrasonography and echocardiography findings, inflammatory syndromes such as Kawasaki's disease, multisystem inflammatory syndrome in children, or MIS C, or macrophage activation syndrome are higher on the differential.

Some of the systemic viral infections remain a possibility, such as EBV virus, um, and adenovirus.

I think Febrile episode number 96 in April was about Kawasaki's disease, so I think that is less likely.

Bacterial infections related to vasculitis like murine typhus, Rocky Mountain spotted fever should still be considered, especially with the right epidemiological history.

An unusually severe case of cat scratch may still be on the list as well.

At this point, with the echocardiogram findings, it'll be difficult to exclude Kawasaki's disease, and we would consider asking our cardiology and rheumatology colleagues for help while we continue our infectious disease evaluation for murine typhus, and cat scratch disease.So, Gaby, what did we find?

So, back to our patient, we found a typhus IgG antibody of 1:64 and then typhus IgM antibody of 1:128.

Before this result was obtained, since the presentation of the patient was concerning for FUO, a Karius testing was sent and it resulted positive for typhus as well.

So, finally after two weeks after her symptoms started, our patient was started on doxycycline.

She did also receive IVIG because of this coronary dilation that we found, uh, per rheumatology and concerns about atypical Kawasaki disease.

The serologies were, of course, obtained before the IVIG was given.

So at this point, she also had an MRI of her chest, abdomen, and pelvis, which showed interval resolution of the previously visualized feeling defect within the abdominal aorta that was seen in the aortic ultrasound.

They still reported a trace left pleural effusion and a trace pericardial effusion as well, and free fluid in the pelvis.

Then a two week echo repeat was normal, and the mid left main coronary artery size, which was improved compared to the prior study taken a week before.

So we saw her in clinic about a month after she was discharged and the typhus IgM result at that visit came back at 1:256.

While our patient did receive treatment for Kawasaki disease, we felt that this patient had a very unusual, severe case of murine typhus, especially with the serologies and even the Karius being positive.

So Dr.

Ellsworth, in your experience, how common is murine typhus and how is it transmitted?

Murine typhus, also known as endemic typhus or flea borne typhus, is caused by Rickettsia typhi.

The primary way that it spreads among rats and then to humans is through flea bites, although other flea species can also carry it.

Fleas become lifelong carriers after biting infected rats, which are the natural host for Rickettsia typhi.

Interestingly, possums and feral cats have become significant sources of murine typhus in the United States, especially in suburban areas where cat fleas play a role.

The same flea also spreads Rickettsia felis, which causes a syndrome that looks just like Rickettsia typhi.

Transmission happens through the flea feces, which contaminates wounds or enters through the broken skin from flea bites, and there's even a possibility of inhalation of the fecal material.

Murine typhus is found worldwide, particularly in warm climates with lots of rats, cats, or possums and their associated flea populations.

While cases can occur year round, in the U.

S., most are reported from April to October in places like Southern California, Southern Texas, the Southeastern Gulf Coast, and Hawaii.

Interestingly, it tends to affect adult males more often.

In children, though, both boys and girls get it equally, although they might not realize they've been bitten by fleas, which often leads to underdiagnosis.

Back in the 1940s, the U.

S.

saw a big drop in reported cases thanks to using DDT to control fleas.

However, since murine typhus was removed from the list of diseases that doctors must report nationally in 1987, the true number of cases today is uncertain.

Texas, where it's still a reportable disease, saw a notable increase from 157 cases in 2008 to over 500 a year from 2017 to 2019, peaking at 730 cases in 2018.

But even with those numbers, studies suggest there are likely more cases that aren't being diagnosed, especially in places where the disease is common.

A study done by Purcell and colleagues in South Texas looked at antibodies for typhus in 513 kids aged one to 17, and found about 13 percent of them had antibodies.

This tells us that there could be a lot more cases out there than what's being reported.

It's likely that we're missing quite a few because of how tricky the disease can be to spot.

So in your, again, what you typically see is murine typhus, a common explanation for FUO.

And what does the typical murine typhus case look like?

Do you think this case is unusual?

How does murine typhus cause symptoms

Rickettsia typhi is a gram-negative, obligate intracellular bacteria that infects systemic vascular endothelial cells resulting in inflammatory, lymphohistiocytic vasculitis, and vascular injury that may affect any organ.

And this is what leads to the typical clinical and laboratory findings that we see in our patients.

As we stated earlier, murine typhus is often missed due to its nonspecific presentation, typically its uncomplicated clinical course.

Again, most people do not recall flea bites or flea infestations, like in our patient who could not recall any exposures.

Symptoms start within 3 days to 2 weeks after contact with the infected flea, and typical symptoms include fever, headache, body aches, and muscle pain.

A maculopapular rash appears around the end of the first week of illness and occurs in around 50 percent of patients.

The rash is usually on the patient's trunk, although extremities can be involved, including the palms and soles.

About 10 percent of patients may even present with petechiae.

It's important to note that the lack of rash should not exclude the diagnosis of murine typhus.

The classic triad of fever, headache, and rash only occurs in one third to one half of patients.

Common laboratory abnormalities include elevated liver enzymes, elevated LDH, thrombocytopenia, and a high sedimentation rate (ESR).

Murine typhus is typically self limited and resolves in one to two weeks.

In our region, anecdotally, I would say that murine typhus and cat scratch disease are high yield tests for us when evaluating patients with fever of unknown origin.

This was certainly an unusually severe case, though complications of murine typhus have been reported in up to 30 percent of cases, with severe disease occurring more often in adults.

The most common complications include pulmonary issues such as pneumonia, pulmonary effusion, respiratory failure, followed by central nervous system involvement, such as altered level of consciousness, meningitis, seizures, ataxia, and acute kidney injury.

Less frequently reported complications include DIC, septic shock, or multi organ failure, and hemophagocytic syndrome.

Severe hemolysis has been reported in patients with glucose 6 phosphate dehydrogenase deficiency, hemoglobinopathies, and thalassemia.

Overall, about 5-10% of cases require ICU admission, and overall case fatality rate is estimated to be 0.

4%.

Data from Whiteford et al.

suggest that a substantial portion of pediatric patients had severe illness characterized by a febrile interval of 14 days or more, that was 23 percent of patients, or hospitalization of 7 days or more, that was 36 percent of patients.

Once the appropriate therapy has been initiated, which we'll talk about in a bit, most patients defervesce rapidly within 1-3 days.

Given the broad differential diagnosis, it seems like there could be a diagnostic confusion.

Michael, as our diagnostic and antimicrobial steward expert, you actually published an article about MIS C versus typhus, right?

Right.

Common symptoms of typhus are primarily symptoms of systemic inflammation and systemic vasculitis.

And so the common symptoms that Dr.

Ellsworth just discussed, that's a really broad differential diagnosis, uh, like we went over, overlapping with many infectious syndromes as well as non infectious syndromes like Kawasaki disease or MIS C.

And so, just to quickly review, the most common method for the diagnosis of murine typhus are paired acute and convalescent serologies, which our patient had and confirmed a diagnosis of acute murine typhus.

But immunohistochemical staining and PCR in tissue can be performed by select labs.

And in this case, Karius testing was positive, but very little data is actually available on the performance of that test for the diagnosis of murine typhus.

So with all that said, we had a really interesting experience at the start of the SARS CoV 2 pandemic, where we suddenly had several previously healthy patients presenting with signs of systemic inflammation with elevated C reactive protein, triglycerides, procalcitonin, ferritin, as well as liver inflammation.

And they all had fever and rash.

And this was just a few weeks after the first publications about MIS C or PIMS TS were coming out of Europe.

And so the Pediatric ID Service was actually consulted to see these patients for concerns of MIS C.

Our fellow at the time, Dr.

Zain Al Amarat, who's now a PEDS ID faculty at UAMS in Arkansas, uh, was concerned though, because in our region at the time, the incidence of SARS CoV 2 was still quite low that we knew of.

And so we had started testing everyone at the time and none of these patients tested positive or had known exposures to patients or people with positive SARS CoV 2 tests.

And so Dr.

Alamarat obtained a thorough history and discovered that all the patients had dog exposures, several with known fleas.

Again, being the excellent clinician that she is, she also noted that the WBC counts, the white blood cell counts, and platelets were on the low side or the low end of normal.

And so what she suspected was happening was that we were actually having an increased incidence of murine typhus, which we were able to confirm with serologic testing.

And so she was able to summarize all these findings and this experience in an article published in the Pediatric Infectious Diseases Journal.

And what's even more interesting is that our friends, Dr.

Andrea Dean down the street from us at Texas Children's Hospital also reported the same experience at the same time and also published in another journal.

To this day, neither our friends down the street at Texas Children's or here at Memorial Hermann, we're still not sure why this happened and why we had a spike.

We, you know, speculate that maybe it's because kids were out of school because of school closures, or more people were outside with their pets because, you know, being outside was a lower risk of transmission , or maybe because of the media attention, paid to MISC, maybe more parents were seeking medical attention.

Dr.

Chang, what is considered as first line treatment for typhus?

So to date, there are actually no clinical trials conducted regarding the treatment of murine typhus.

Recommendations are based on the analysis of retrospective studies.

So doxycycline is the treatment of choice regardless of patient age, and early diagnosis is usually based on clinical suspicion and epidemiology.

Treatment should not be withheld awaiting confirmatory laboratory results in order to avoid severe and potentially fatal complications.

So, there is this, like, deeply rooted aversion to prescribing doxycycline for pregnant women and pediatric patients less than 8 years old.

You'll recall, maybe, that tetracyclines were discovered in the 1940s and have broad spectrum activity against many types of bacterial pathogens.

And they're actually the drug of choice for tick and flea based infections like murine typhus, Rocky Mountain spotted fever, and ehrlichiosis.

So, why is there this aversion to doxycycline in children and pregnant women?

Well, tetracycline, we know, binds to calcium, which can stain permanent teeth in children and potentially inhibit bone growth to a degree.

In mouse models, it did lead to skeletal problems in mouse embryos when given 11 times the human dose.

But we also know that tetracyclines can cross the placenta.

And so, because of this historical information, tetracyclines were not used in pregnant women.

women nor for children under the age of eight years until all their permanent teeth were in.

But, I think it's important to remember that doxycycline is not tetracycline.

Doxycycline was actually a second generation drug synthesized in 1972.

It has decreased calcium binding, but unfortunately there's really no clinical data in pregnancy for doxycycline.

And so the FDA currently says that there have been no published human data showing that fetal exposure to doxycycline causes cosmetic staining of the primary teeth.

However, this cannot be ruled out because of the tetracycline class effect, quote.

Which is to say that because doxycycline is in the tetracycline class, we don't know for sure because we don't have any data.

They also say that there's no data to prove that doxycycline is safe, but also cite a review of the teratogen information system at the University of Washington School of Public Health, which is considered a global reference for teratogenic safety, which suggests that normal doses of doxycycline during pregnancy are unlikely to pose a

risk, so lacking evidence for harm, it's important to note that doxycycline is recommended as the first line drug in pregnancy for post exposure prophylaxis for anthrax.

So for kids, there is at least one published study from 2007 from Volovitz, uh, et al.

titled, The Absence of Two Staining with Doxycycline Treatment in Young Children, in which the authors tried to make the title as clear as possible related to their findings.

But interestingly, even seven years after the publication of that article, clinicians were still hesitant to give doxycycline to patients less than eight years of age.

And this was described in another paper, uh, Zientek et al, uh, and that paper was called The Self-Reported Treatment Practices by Healthcare Providers Could Lead To Death from Rocky Mountain Spotted Fever.

And this survey worryingly showed that for kids under the age of eight years of age, providers were not prescribing doxycycline, which is the drug of choice, when concerned about Rocky Mountain spotted fever, despite the fact that pediatric patients less than nine years of age have the highest case fatality rate of any age group for Rocky Mountain spotted fever.

And so one of the leading factors to mortality in Rocky Mountain spotted fever is delay in diagnosis and delay in initiation of appropriate therapy with doxycycline.

So this actually got the attention of the CDC and this concerned them so much that the next year, the CDC, in a paper in 2015, Todd et al.

published a paper called No Visible Dental Staining in Children Treated with Doxycycline for Suspected Rocky Mountain Spotted Fever.

And so I think they were just trying to be very, very clear that you should be giving doxycycline when you're worried about tick or flea borne illnesses as empiric therapy.

And so, the takeaway of all of this is please do not hesitate to prescribe doxycycline in children if you suspect a vector borne illness like murine typhus or Rocky Mountain spotted fever.

So just to summarize and confirm, it is okay to use doxycycline in children?

Yes, absolutely.

And just to emphasize again, you should definitely not withhold treatment while awaiting laboratory confirmation of murine typhus or other vector borne illnesses.

And so once you do start the doxycycline, though, fever resolves quickly, usually one to three days after starting therapy, and with clinical improvement, treatment should be continuing for at least three days after the patient becomes afebrile, and the total treatment course is usually seven to fourteen days.

So, what can we do to decrease the transmission of typhus, particularly in endemic zones like us?

From what is known, we do think that prior infection provides lasting immunity, but there's no vaccine for murine typhus.

So the key here really is avoidance and elimination of flea vectors and rodent infested areas.

And as we mentioned previously, the U.

S.

was successful in reducing the incidence of murine typhus with the pesticide DDT to control flea vectors, but obviously, with the unintended consequences of DDT.

So that said, you still have to control the fleas before hosts, as fleas can easily find other hosts, as in Texas, where it seems that in addition to rodents, the possums and feral cats that Dr.

Ellsworth mentioned are playing a role in transmission.

Always, though, flea control is easier said than done, but if you have pets, you definitely want to make sure you clean areas where fleas can breed, like pet bedding, rugs.

You want to treat your pets per your vet[eranarian]'s instructions and, potentially calling a pest control expert if you're having a lot of problems.

Uh, and this may take several cycles and potentially months to achieve.

You can also minimize possum and rodent exposure by making sure your waste bins are secured, make sure your sandboxes are covered to avoid feral cats using them as litter boxes, and yeah.

And so I think typhus is a super cool infection because it really shows the complex interactions between human behavior, societal structures, and nature that allow infections to propagate.

What a great finale.

And thank you guys so much for sharing this.

I've never had a case of murine typhus, so I definitely learned a lot.

And to help us wrap up, maybe Gaby, could you summarize with a few take home points?

Yes, sure, so I would say first to just keep in mind that a few patients with murine typhus can actually recall having a flea exposure or infestation with fleas.

So obviously getting a good history is important, but even if you don't get that exposure and the symptoms are consistent, just have that diagnosis in the back of your mind.

Then I would, I would also say that remember, very few patients have all the classic symptoms.

So symptoms can be very non specific.

And then as soon as you, as you're thinking about the diagnosis, just go ahead and start doxycycline, regardless of the age, and just don't hesitate if you're suspecting this.

And, don't wait for labs to be resulted before starting.

A big thanks to Gaby, Misti, and Michael for joining Febrile.

Don't forget to check out the website febrilepodcast.

com where you'll find the Consult Notes which are written in complements to the episodes with links to references, our library of ID infographics, and a link to our merch store.

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Thanks for listening, stay safe, and I'll see you next time.