1 00:00:06,620 --> 00:00:11,379 Sara Dong: Hi everyone, welcome to Febrile, a cultured podcast about all things infectious disease. 2 00:00:11,950 --> 00:00:16,899 We use consult questions to dive into ID clinical reasoning, diagnostics, and antimicrobial management. 3 00:00:17,400 --> 00:00:20,349 I'm Sara Dong, your host and a MedPeds ID doc. 4 00:00:20,900 --> 00:00:29,700 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. 5 00:00:30,119 --> 00:00:32,100 First up, I'll introduce our host, Dr. 6 00:00:32,100 --> 00:00:33,750 Maria Gabriela Segura. 7 00:00:33,910 --> 00:00:38,140 She is a third year pediatric infectious diseases fellow at UTHealth Houston. 8 00:00:38,189 --> 00:00:45,819 Gaby Segura: Hi, I go by Gaby and I'm very grateful for being here today and excited to record this episode with you. 9 00:00:46,220 --> 00:00:47,640 Sara Dong: She is joined by two discussants. 10 00:00:48,590 --> 00:00:48,940 Dr. 11 00:00:48,940 --> 00:00:54,510 Misti Ellsworth is an Associate Professor of Pediatrics and Director of Pediatric Infection Prevention. 12 00:00:54,780 --> 00:00:58,670 Misti Ellsworth: Hi, I'm Misti Ellsworth, and I'm excited to be here today on the Febrile podcast. 13 00:00:59,590 --> 00:01:00,480 Sara Dong: We also have Dr. 14 00:01:00,480 --> 00:01:06,209 Michael Chang, an Assistant Professor of Pediatrics and Co Director of the Pediatric Antimicrobial Stewardship Program. 15 00:01:06,789 --> 00:01:11,180 Michael Chang: Hi, I'm Michael Chang, and I'm also very excited to be here today. 16 00:01:11,749 --> 00:01:17,720 Sara Dong: So, before we jump into the case, we always ask our one question as everyone's favorite cultured podcast. 17 00:01:17,850 --> 00:01:25,099 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. 18 00:01:25,130 --> 00:01:26,669 So, Gaby, maybe I'll start with you. 19 00:01:26,899 --> 00:01:27,220 Gaby Segura: Yes. 20 00:01:27,460 --> 00:01:33,399 Yeah, we were talking about this a lot, really, like, outside of work, for me, I like to run. 21 00:01:33,850 --> 00:01:37,509 I do like to watch a lot of Netflix and HBO shows. 22 00:01:38,400 --> 00:01:41,289 The main thing is spending time with my kids. 23 00:01:41,289 --> 00:01:44,270 I have two boys, a seven year old and a two year old. 24 00:01:44,820 --> 00:01:52,230 We like to travel, mostly to beach destinations, and pretty much doing anything with my husband and my kids is my outside thing 25 00:01:53,370 --> 00:01:53,770 Sara Dong: Love it. 26 00:01:54,330 --> 00:01:54,680 Love it. 27 00:01:54,780 --> 00:01:55,670 What about you, Misty? 28 00:01:55,970 --> 00:02:02,530 Misti Ellsworth: So, I was super excited this week that The Bear Season 3 came out on Hulu, so pumped about that. 29 00:02:02,570 --> 00:02:07,120 And then I've been reading Agatha Christie novels because it's too hot to go outside. 30 00:02:08,619 --> 00:02:13,050 Sara Dong: Yeah, I have the new season of The Bear queued up, but hopefully I'll start some of them this weekend. 31 00:02:13,150 --> 00:02:13,710 I'm excited. 32 00:02:14,440 --> 00:02:15,630 And you, Michael, what do you have? 33 00:02:16,210 --> 00:02:26,869 Michael Chang: 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. 34 00:02:27,900 --> 00:02:32,359 So I, there's a band from London called The Last Dinner Party. 35 00:02:32,840 --> 00:02:37,640 And I think that was like the first album I had listened to that wasn't K pop in like months. 36 00:02:37,910 --> 00:02:39,260 It was such a breath of fresh air. 37 00:02:39,260 --> 00:02:41,370 And I was like, Oh my God, I didn't even know I needed this. 38 00:02:41,870 --> 00:02:47,480 And so I probably listened to that album twice a week, all the way through like every week since like January. 39 00:02:47,480 --> 00:02:48,309 It's so good. 40 00:02:48,340 --> 00:02:48,580 Yeah. 41 00:02:48,580 --> 00:02:52,160 They're like a, kind of a rock theatrical group. 42 00:02:52,190 --> 00:02:52,820 All women. 43 00:02:52,840 --> 00:02:53,940 It's awesome. 44 00:02:54,080 --> 00:02:57,710 So, uh, highly recommend if you've never heard of The Last Dinner Party, check them out. 45 00:02:58,650 --> 00:02:59,100 Sara Dong: I love it. 46 00:02:59,180 --> 00:03:03,340 Um, well, I am going to hand it over to Gaby who's going to lead us through today. 47 00:03:03,370 --> 00:03:06,950 It sounds like you had a case of fever of unknown origin. 48 00:03:07,060 --> 00:03:07,340 Gaby Segura: Yes. 49 00:03:07,730 --> 00:03:20,475 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. 50 00:03:20,945 --> 00:03:26,665 In the middle of winter in the Texas Gulf Coast region, she started having fevers and decreased energy. 51 00:03:26,865 --> 00:03:28,845 Mom says like she wouldn't get out of bed. 52 00:03:28,925 --> 00:03:31,105 She was doing Tylenol as needed. 53 00:03:31,585 --> 00:03:39,125 It improved the symptoms for a little bit and then she would again feel very tired and having non quantified temperatures, uh, fever. 54 00:03:39,840 --> 00:03:42,850 On the second day, mom took her to an urgent care. 55 00:03:43,040 --> 00:03:46,550 They did, they swapped her for strep throat, COVID, and flu. 56 00:03:46,800 --> 00:03:47,890 Everything was negative. 57 00:03:48,590 --> 00:03:53,800 So that same afternoon at home, she had a temperature that they quantified to 101 F. 58 00:03:53,860 --> 00:04:00,344 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. 59 00:04:01,165 --> 00:04:09,595 PCP diagnosed her with left otitis media and prescribed amoxicillin, which she was taking but didn't really improve at any point with it. 60 00:04:10,285 --> 00:04:21,975 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. 61 00:04:22,075 --> 00:04:23,555 All of them were normal. 62 00:04:23,955 --> 00:04:26,988 While she was on the ED, her temperature went up to 102. 63 00:04:26,988 --> 00:04:28,358 7 F. 64 00:04:28,388 --> 00:04:38,875 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. 65 00:04:39,475 --> 00:04:49,435 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. 66 00:04:50,245 --> 00:05:00,305 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. 67 00:05:01,055 --> 00:05:09,900 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. 68 00:05:10,040 --> 00:05:14,830 They got a blood culture and a urine culture, and then she was brought up to the floor. 69 00:05:15,980 --> 00:05:27,170 So for her past history, her birth history was unremarkable, no pertinent past medical history, no surgeries, and family history was also unremarkable. 70 00:05:27,300 --> 00:05:29,270 Her immunizations were up to date. 71 00:05:29,850 --> 00:05:36,990 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. 72 00:05:37,350 --> 00:05:43,780 Mom stays at home, dad works in carpet installations, they both go to school, both sisters. 73 00:05:44,030 --> 00:05:47,610 There were no sick contacts or no other exposures in the history. 74 00:05:48,220 --> 00:05:51,760 So, when we saw her the first time, her vital signs were unremarkable. 75 00:05:51,820 --> 00:05:53,980 She was afebrile at that point and on room air. 76 00:05:54,670 --> 00:06:03,130 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. 77 00:06:03,230 --> 00:06:06,450 And mom had said that it, she's had that in the past. 78 00:06:06,790 --> 00:06:13,380 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. 79 00:06:14,090 --> 00:06:18,210 And then she didn't have any edema in upper extremities or no skin peeling. 80 00:06:18,300 --> 00:06:23,110 Nothing in throat, ears, no lymph nodes were present at that time. 81 00:06:23,885 --> 00:06:32,145 So, the initial labs that they collected, she, uh, had a mild anemia with a hemoglobin of 11.9, mild thrombocytopenia of 156. 82 00:06:33,420 --> 00:06:42,520 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. 83 00:06:43,210 --> 00:06:47,180 And her CMP had a mildly elevated AST to 111. 84 00:06:47,750 --> 00:07:03,520 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. 85 00:07:03,900 --> 00:07:05,690 This is the case that we have. 86 00:07:05,730 --> 00:07:08,270 So based on this presentation, Dr. 87 00:07:08,270 --> 00:07:12,050 Ellsworth, what are you, what would be your differentials so far? 88 00:07:12,140 --> 00:07:26,690 Misti Ellsworth: 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. 89 00:07:27,640 --> 00:07:31,610 And she's also been taking oral amoxicillin with really no improvement in her symptoms. 90 00:07:32,295 --> 00:07:37,685 Overall, I'd say our symptoms are non specific, and, you know, it could really be caused by multiple different infections. 91 00:07:38,335 --> 00:07:46,845 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. 92 00:07:47,495 --> 00:07:59,620 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. 93 00:08:00,120 --> 00:08:10,980 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. 94 00:08:11,930 --> 00:08:23,800 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. 95 00:08:23,970 --> 00:08:35,800 Despite the cough with primarily nonspecific systemic symptoms, she could have a developing septic arthritis or osteomyelitis secondary to Staph aureus or Kingella. 96 00:08:35,970 --> 00:08:38,890 However, Kingella is less likely given her age. 97 00:08:39,570 --> 00:08:45,180 So urinary tract infections and urosepsis should be considered, but her testing was reported to be negative. 98 00:08:45,860 --> 00:08:56,510 Uncommon, but meningococcal infections, and with the appropriate epidemiologic factors like travel, consider typhoid, leptospirosis, but both these would be rare. 99 00:08:57,480 --> 00:09:05,390 At 11 years of age, it's also worthwhile to obtain a sexual history, consider infections such as disseminated gonococcal infection or syphilis. 100 00:09:06,080 --> 00:09:09,990 Acute HIV could present with nonspecific symptoms as well. 101 00:09:10,770 --> 00:09:15,340 Um, in our region, we also should always consider some vector borne illnesses. 102 00:09:16,195 --> 00:09:29,475 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. 103 00:09:30,445 --> 00:09:39,490 Other nonspecific manifestations can include myalgias, malaise, nausea, vomiting, and abdominal pain with tenderness in more than half of the cases. 104 00:09:39,490 --> 00:09:52,430 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. 105 00:09:53,200 --> 00:09:59,480 So sometimes in our region, we do see things that are considered tropical illnesses, so we should put that on our differential too. 106 00:09:59,480 --> 00:10:06,110 So things like Zika, dengue, and possibly malaria if we find the right risk factors or history. 107 00:10:06,310 --> 00:10:18,210 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. 108 00:10:18,870 --> 00:10:22,375 Gaby, I think additional imaging and echocardiogram can help us. 109 00:10:22,765 --> 00:10:25,885 Also, is there any additional history that might be helpful? 110 00:10:26,235 --> 00:10:26,605 Gaby Segura: Yes. 111 00:10:26,785 --> 00:10:30,835 So, for imaging, we have a chest x ray that was normal. 112 00:10:31,215 --> 00:10:34,505 We had an echo done on the 11th day of illness. 113 00:10:34,565 --> 00:10:36,285 This was read as normal too. 114 00:10:36,785 --> 00:10:44,205 And then we got an abdominal ultrasound, of course, part of FUO workup as well, that showed non occlusive thrombus within the mid aorta. 115 00:10:44,390 --> 00:10:52,380 There was some, uh, trace left pleural effusion, hepatomegaly with left kidney above the second standard deviation for her age. 116 00:10:52,550 --> 00:11:07,580 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. 117 00:11:08,260 --> 00:11:17,215 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. 118 00:11:17,235 --> 00:11:34,665 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. 119 00:11:35,770 --> 00:11:52,500 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. 120 00:11:52,550 --> 00:11:53,890 All of those were normal. 121 00:11:54,980 --> 00:12:00,230 So what do you think we should have in consideration with this information as a differential diagnosis? 122 00:12:00,850 --> 00:12:10,020 Misti Ellsworth: So, the normal chest radiograph doesn't exclude but does make community acquired pneumonia less likely, especially with the later onset of her cough. 123 00:12:10,580 --> 00:12:14,850 A viral or respiratory tract infection also seems less likely. 124 00:12:15,510 --> 00:12:30,210 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. 125 00:12:30,800 --> 00:12:36,670 Some of the systemic viral infections remain a possibility, such as EBV virus, um, and adenovirus. 126 00:12:37,310 --> 00:12:43,220 I think Febrile episode number 96 in April was about Kawasaki's disease, so I think that is less likely. 127 00:12:43,820 --> 00:12:52,900 Bacterial infections related to vasculitis like murine typhus, Rocky Mountain spotted fever should still be considered, especially with the right epidemiological history. 128 00:12:53,420 --> 00:12:57,260 An unusually severe case of cat scratch may still be on the list as well. 129 00:12:57,480 --> 00:13:13,825 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? 130 00:13:14,285 --> 00:13:26,315 Gaby Segura: So, back to our patient, we found a typhus IgG antibody of 1:64 and then typhus IgM antibody of 1:128. 131 00:13:26,475 --> 00:13:39,755 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. 132 00:13:39,995 --> 00:13:46,075 So, finally after two weeks after her symptoms started, our patient was started on doxycycline. 133 00:13:46,625 --> 00:13:55,975 She did also receive IVIG because of this coronary dilation that we found, uh, per rheumatology and concerns about atypical Kawasaki disease. 134 00:13:56,675 --> 00:14:00,355 The serologies were, of course, obtained before the IVIG was given. 135 00:14:00,825 --> 00:14:16,230 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. 136 00:14:16,710 --> 00:14:24,590 They still reported a trace left pleural effusion and a trace pericardial effusion as well, and free fluid in the pelvis. 137 00:14:24,870 --> 00:14:35,630 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. 138 00:14:36,640 --> 00:14:47,380 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. 139 00:14:47,780 --> 00:14:59,780 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. 140 00:14:59,830 --> 00:15:00,720 So Dr. 141 00:15:00,720 --> 00:15:06,830 Ellsworth, in your experience, how common is murine typhus and how is it transmitted? 142 00:15:06,850 --> 00:15:13,290 Misti Ellsworth: Murine typhus, also known as endemic typhus or flea borne typhus, is caused by Rickettsia typhi. 143 00:15:13,700 --> 00:15:21,110 The primary way that it spreads among rats and then to humans is through flea bites, although other flea species can also carry it. 144 00:15:21,290 --> 00:15:27,270 Fleas become lifelong carriers after biting infected rats, which are the natural host for Rickettsia typhi. 145 00:15:27,940 --> 00:15:36,240 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. 146 00:15:36,995 --> 00:15:43,085 The same flea also spreads Rickettsia felis, which causes a syndrome that looks just like Rickettsia typhi. 147 00:15:43,725 --> 00:15:54,255 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. 148 00:15:54,425 --> 00:16:02,335 Murine typhus is found worldwide, particularly in warm climates with lots of rats, cats, or possums and their associated flea populations. 149 00:16:03,015 --> 00:16:05,345 While cases can occur year round, in the U. 150 00:16:05,345 --> 00:16:13,255 S., most are reported from April to October in places like Southern California, Southern Texas, the Southeastern Gulf Coast, and Hawaii. 151 00:16:13,805 --> 00:16:16,835 Interestingly, it tends to affect adult males more often. 152 00:16:17,495 --> 00:16:24,255 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. 153 00:16:25,310 --> 00:16:26,740 Back in the 1940s, the U. 154 00:16:26,740 --> 00:16:26,880 S. 155 00:16:27,080 --> 00:16:31,690 saw a big drop in reported cases thanks to using DDT to control fleas. 156 00:16:32,300 --> 00:16:41,240 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. 157 00:16:41,850 --> 00:16:55,715 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. 158 00:16:56,425 --> 00:17:03,715 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. 159 00:17:04,365 --> 00:17:16,045 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. 160 00:17:16,635 --> 00:17:20,165 This tells us that there could be a lot more cases out there than what's being reported. 161 00:17:20,555 --> 00:17:25,215 It's likely that we're missing quite a few because of how tricky the disease can be to spot. 162 00:17:25,725 --> 00:17:32,465 Gaby Segura: So in your, again, what you typically see is murine typhus, a common explanation for FUO. 163 00:17:32,725 --> 00:17:35,495 And what does the typical murine typhus case look like? 164 00:17:35,605 --> 00:17:37,625 Do you think this case is unusual? 165 00:17:37,925 --> 00:17:40,205 How does murine typhus cause symptoms 166 00:17:40,800 --> 00:17:55,180 Misti Ellsworth: 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. 167 00:17:55,720 --> 00:18:00,310 And this is what leads to the typical clinical and laboratory findings that we see in our patients. 168 00:18:00,805 --> 00:18:08,635 As we stated earlier, murine typhus is often missed due to its nonspecific presentation, typically its uncomplicated clinical course. 169 00:18:09,375 --> 00:18:15,795 Again, most people do not recall flea bites or flea infestations, like in our patient who could not recall any exposures. 170 00:18:16,405 --> 00:18:26,235 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. 171 00:18:27,175 --> 00:18:33,935 A maculopapular rash appears around the end of the first week of illness and occurs in around 50 percent of patients. 172 00:18:34,775 --> 00:18:40,284 The rash is usually on the patient's trunk, although extremities can be involved, including the palms and soles. 173 00:18:41,235 --> 00:18:44,245 About 10 percent of patients may even present with petechiae. 174 00:18:44,985 --> 00:18:49,525 It's important to note that the lack of rash should not exclude the diagnosis of murine typhus. 175 00:18:50,435 --> 00:18:56,045 The classic triad of fever, headache, and rash only occurs in one third to one half of patients. 176 00:18:56,895 --> 00:19:05,385 Common laboratory abnormalities include elevated liver enzymes, elevated LDH, thrombocytopenia, and a high sedimentation rate (ESR). 177 00:19:05,450 --> 00:19:09,930 Murine typhus is typically self limited and resolves in one to two weeks. 178 00:19:10,570 --> 00:19:19,800 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. 179 00:19:20,145 --> 00:19:31,215 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. 180 00:19:32,015 --> 00:19:48,325 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. 181 00:19:48,825 --> 00:19:56,225 Less frequently reported complications include DIC, septic shock, or multi organ failure, and hemophagocytic syndrome. 182 00:19:56,865 --> 00:20:05,465 Severe hemolysis has been reported in patients with glucose 6 phosphate dehydrogenase deficiency, hemoglobinopathies, and thalassemia. 183 00:20:06,225 --> 00:20:13,785 Overall, about 5-10% of cases require ICU admission, and overall case fatality rate is estimated to be 0. 184 00:20:13,785 --> 00:20:14,495 4%. 185 00:20:14,495 --> 00:20:16,265 Data from Whiteford et al. 186 00:20:16,375 --> 00:20:31,195 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. 187 00:20:31,705 --> 00:20:39,225 Once the appropriate therapy has been initiated, which we'll talk about in a bit, most patients defervesce rapidly within 1-3 days. 188 00:20:39,820 --> 00:20:44,850 Gaby Segura: Given the broad differential diagnosis, it seems like there could be a diagnostic confusion. 189 00:20:45,000 --> 00:20:52,810 Michael, as our diagnostic and antimicrobial steward expert, you actually published an article about MIS C versus typhus, right? 190 00:20:53,080 --> 00:20:53,520 Michael Chang: Right. 191 00:20:53,590 --> 00:20:58,999 Common symptoms of typhus are primarily symptoms of systemic inflammation and systemic vasculitis. 192 00:20:59,150 --> 00:21:00,910 And so the common symptoms that Dr. 193 00:21:00,910 --> 00:21:11,470 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. 194 00:21:11,520 --> 00:21:23,610 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. 195 00:21:23,610 --> 00:21:28,190 But immunohistochemical staining and PCR in tissue can be performed by select labs. 196 00:21:28,600 --> 00:21:36,310 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. 197 00:21:36,930 --> 00:21:54,795 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. 198 00:21:55,135 --> 00:21:56,775 And they all had fever and rash. 199 00:21:57,235 --> 00:22:03,735 And this was just a few weeks after the first publications about MIS C or PIMS TS were coming out of Europe. 200 00:22:03,735 --> 00:22:09,345 And so the Pediatric ID Service was actually consulted to see these patients for concerns of MIS C. 201 00:22:09,925 --> 00:22:11,575 Our fellow at the time, Dr. 202 00:22:11,575 --> 00:22:23,615 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. 203 00:22:23,995 --> 00:22:34,285 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. 204 00:22:34,985 --> 00:22:35,575 And so Dr. 205 00:22:35,575 --> 00:22:42,175 Alamarat obtained a thorough history and discovered that all the patients had dog exposures, several with known fleas. 206 00:22:42,675 --> 00:22:51,905 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. 207 00:22:52,285 --> 00:23:00,175 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. 208 00:23:00,440 --> 00:23:06,510 And so she was able to summarize all these findings and this experience in an article published in the Pediatric Infectious Diseases Journal. 209 00:23:06,870 --> 00:23:09,560 And what's even more interesting is that our friends, Dr. 210 00:23:09,560 --> 00:23:17,730 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. 211 00:23:18,065 --> 00:23:26,015 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. 212 00:23:26,385 --> 00:23:42,315 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. 213 00:23:42,655 --> 00:23:43,045 Gaby Segura: Dr. 214 00:23:43,045 --> 00:23:46,255 Chang, what is considered as first line treatment for typhus? 215 00:23:46,725 --> 00:23:51,885 Michael Chang: So to date, there are actually no clinical trials conducted regarding the treatment of murine typhus. 216 00:23:52,315 --> 00:23:55,965 Recommendations are based on the analysis of retrospective studies. 217 00:23:56,425 --> 00:24:04,695 So doxycycline is the treatment of choice regardless of patient age, and early diagnosis is usually based on clinical suspicion and epidemiology. 218 00:24:05,055 --> 00:24:11,435 Treatment should not be withheld awaiting confirmatory laboratory results in order to avoid severe and potentially fatal complications. 219 00:24:11,860 --> 00:24:19,330 So, there is this, like, deeply rooted aversion to prescribing doxycycline for pregnant women and pediatric patients less than 8 years old. 220 00:24:19,859 --> 00:24:27,390 You'll recall, maybe, that tetracyclines were discovered in the 1940s and have broad spectrum activity against many types of bacterial pathogens. 221 00:24:27,800 --> 00:24:34,220 And they're actually the drug of choice for tick and flea based infections like murine typhus, Rocky Mountain spotted fever, and ehrlichiosis. 222 00:24:35,090 --> 00:24:39,430 So, why is there this aversion to doxycycline in children and pregnant women? 223 00:24:39,865 --> 00:24:47,605 Well, tetracycline, we know, binds to calcium, which can stain permanent teeth in children and potentially inhibit bone growth to a degree. 224 00:24:48,024 --> 00:24:54,745 In mouse models, it did lead to skeletal problems in mouse embryos when given 11 times the human dose. 225 00:24:55,105 --> 00:24:57,995 But we also know that tetracyclines can cross the placenta. 226 00:24:58,435 --> 00:25:03,355 And so, because of this historical information, tetracyclines were not used in pregnant women. 227 00:25:03,490 --> 00:25:07,740 women nor for children under the age of eight years until all their permanent teeth were in. 228 00:25:08,360 --> 00:25:13,259 But, I think it's important to remember that doxycycline is not tetracycline. 229 00:25:13,260 --> 00:25:17,320 Doxycycline was actually a second generation drug synthesized in 1972. 230 00:25:17,630 --> 00:25:23,260 It has decreased calcium binding, but unfortunately there's really no clinical data in pregnancy for doxycycline. 231 00:25:24,235 --> 00:25:33,025 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. 232 00:25:33,595 --> 00:25:38,185 However, this cannot be ruled out because of the tetracycline class effect, quote. 233 00:25:38,745 --> 00:25:44,405 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. 234 00:25:45,090 --> 00:26:03,280 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 235 00:26:03,280 --> 00:26:13,290 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. 236 00:26:14,190 --> 00:26:20,150 So for kids, there is at least one published study from 2007 from Volovitz, uh, et al. 237 00:26:20,150 --> 00:26:29,210 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. 238 00:26:29,800 --> 00:26:39,045 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. 239 00:26:39,045 --> 00:26:50,165 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. 240 00:26:50,675 --> 00:27:09,345 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. 241 00:27:09,855 --> 00:27:17,615 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. 242 00:27:18,785 --> 00:27:28,760 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. 243 00:27:28,780 --> 00:27:36,680 published a paper called No Visible Dental Staining in Children Treated with Doxycycline for Suspected Rocky Mountain Spotted Fever. 244 00:27:37,230 --> 00:27:46,960 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. 245 00:27:47,500 --> 00:27:58,330 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. 246 00:27:58,890 --> 00:28:04,650 Gaby Segura: So just to summarize and confirm, it is okay to use doxycycline in children? 247 00:28:05,100 --> 00:28:06,350 Michael Chang: Yes, absolutely. 248 00:28:06,750 --> 00:28:15,630 And just to emphasize again, you should definitely not withhold treatment while awaiting laboratory confirmation of murine typhus or other vector borne illnesses. 249 00:28:15,790 --> 00:28:31,670 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. 250 00:28:32,455 --> 00:28:38,365 Gaby Segura: So, what can we do to decrease the transmission of typhus, particularly in endemic zones like us? 251 00:28:38,855 --> 00:28:45,735 Michael Chang: From what is known, we do think that prior infection provides lasting immunity, but there's no vaccine for murine typhus. 252 00:28:46,425 --> 00:28:52,215 So the key here really is avoidance and elimination of flea vectors and rodent infested areas. 253 00:28:52,695 --> 00:28:54,795 And as we mentioned previously, the U. 254 00:28:54,795 --> 00:28:54,955 S. 255 00:28:55,005 --> 00:29:03,755 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. 256 00:29:03,955 --> 00:29:14,045 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. 257 00:29:14,045 --> 00:29:16,435 Ellsworth mentioned are playing a role in transmission. 258 00:29:16,585 --> 00:29:24,985 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. 259 00:29:25,075 --> 00:29:32,255 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. 260 00:29:32,735 --> 00:29:36,195 Uh, and this may take several cycles and potentially months to achieve. 261 00:29:37,005 --> 00:29:48,110 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. 262 00:29:48,110 --> 00:29:59,405 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. 263 00:30:01,010 --> 00:30:02,050 Sara Dong: What a great finale. 264 00:30:02,080 --> 00:30:04,250 And thank you guys so much for sharing this. 265 00:30:04,300 --> 00:30:08,530 I've never had a case of murine typhus, so I definitely learned a lot. 266 00:30:09,380 --> 00:30:14,190 And to help us wrap up, maybe Gaby, could you summarize with a few take home points? 267 00:30:14,920 --> 00:30:26,320 Gaby Segura: 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. 268 00:30:26,930 --> 00:30:35,605 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. 269 00:30:36,105 --> 00:30:41,385 Then I would, I would also say that remember, very few patients have all the classic symptoms. 270 00:30:41,655 --> 00:30:44,575 So symptoms can be very non specific. 271 00:30:44,865 --> 00:30:56,205 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. 272 00:30:56,245 --> 00:30:59,535 And, don't wait for labs to be resulted before starting. 273 00:31:02,605 --> 00:31:06,075 Sara Dong: A big thanks to Gaby, Misti, and Michael for joining Febrile. 274 00:31:06,275 --> 00:31:08,575 Don't forget to check out the website febrilepodcast. 275 00:31:08,575 --> 00:31:17,855 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. 276 00:31:18,045 --> 00:31:22,655 Febrile is produced with support from the Infectious Diseases Society of America or IDSA. 277 00:31:22,895 --> 00:31:26,925 Please reach out if you have any suggestions for future shows or want to be more involved with Febrile. 278 00:31:27,655 --> 00:31:30,104 Thanks for listening, stay safe, and I'll see you next time.