1 00:00:12,810 --> 00:00:13,680 Sara Dong: Hi everyone. 2 00:00:13,710 --> 00:00:18,120 Welcome to Febrile, a cultured podcast about all things infectious disease. 3 00:00:18,510 --> 00:00:24,180 We use consult questions to dive into ID clinical reasoning, diagnostics, and anti-microbial management. 4 00:00:25,200 --> 00:00:29,270 I'm your host, Sara Dong, a combined adult and pediatric ID fellow. 5 00:00:29,919 --> 00:00:34,530 Here on Febrile, we use patient cases and consult questions to learn about high yield ID topics. 6 00:00:34,769 --> 00:00:39,530 We'll present pieces of the story of a patient's case, and then pause along the way to hear from our guest consultant. 7 00:00:40,050 --> 00:00:44,550 Welcome to the final episode of our Curious Congenital Conundrum series. 8 00:00:44,790 --> 00:00:47,070 I'm excited to introduce our guests today. 9 00:00:47,400 --> 00:00:48,600 Our host is Dr. 10 00:00:48,600 --> 00:00:49,800 Sarah May Johnson. 11 00:00:50,070 --> 00:00:57,000 She is a pediatric registrar of infectious diseases, immunology and bone marrow transplant at Great Ormond Street Hospital in London. 12 00:00:57,300 --> 00:01:03,180 She is also interested in global health and has completed a diploma from the London School of Hygiene and Tropical Medicine. 13 00:01:03,570 --> 00:01:09,630 And she has also been awarded a Wellcome Trust global health research fellowship to explore adolescent tuberculosis. 14 00:01:09,895 --> 00:01:11,804 Our guest discussant today is Dr. 15 00:01:11,804 --> 00:01:12,985 Fani Ladomenou. 16 00:01:13,375 --> 00:01:19,014 She is a consultant in Pediatric ID at the Venizeleion General Hospital in Crete, Greece. 17 00:01:19,225 --> 00:01:28,345 She was previously a fellow in pediatric ID and immunology in the UK, and has worked as a consultant in pediatric immunology and ID also at Great Ormond Street Hospital. 18 00:01:28,935 --> 00:01:35,405 Since then she's been caring for children in Greece and has been responsible for the pediatric ID and immunology service since 2012. 19 00:01:35,525 --> 00:01:39,605 And she's focused her previous research efforts on various pediatric ID topics. 20 00:01:39,845 --> 00:01:50,885 In addition, she has previously served as a Young Board Representative for ESPID or the European Society for Pediatric Infectious Diseases between 2018 and 2021. 21 00:01:51,185 --> 00:01:52,265 Thank you for joining us today. 22 00:01:53,115 --> 00:01:53,654 Sarah May Johnson: Thanks. 23 00:01:53,835 --> 00:01:54,225 Fani Ladomenou: Thank you. 24 00:01:54,225 --> 00:01:55,244 I'm glad I'm here too. 25 00:01:55,544 --> 00:02:00,914 Sara Dong: So before we jump into the case today, which is super interesting, we always like to ask one nonmedical question. 26 00:02:01,304 --> 00:02:06,674 We wanted to see if you'd be willing to share a little piece of culture or something that you have enjoyed recently. 27 00:02:07,924 --> 00:02:08,914 Sarah May Johnson: I'm a big knitter. 28 00:02:08,945 --> 00:02:16,774 So I spent most of my life knitting and for the second time ever, I'm actually knitting a pair of socks because I normally like to do more complex knitwear. 29 00:02:17,135 --> 00:02:22,114 Um, but my boyfriend's been wearing my grandpa's socks around the house and they are eaten to pieces. 30 00:02:22,114 --> 00:02:25,214 So now I'm knitting him some socks and they're literally like that. 31 00:02:25,894 --> 00:02:30,814 It's like a World War II style socks that go up to the knees, kind of like Wellington boots. 32 00:02:32,579 --> 00:02:39,420 Sara Dong: Uh, well, I've only been able to knit a scarf, but never quite moved into anything tubular yet. 33 00:02:39,420 --> 00:02:40,829 So that'll be my next step. 34 00:02:41,369 --> 00:02:43,089 Um, what about you Fani? 35 00:02:44,069 --> 00:02:47,480 Fani Ladomenou: I will talk about, um, it's an old book. 36 00:02:47,480 --> 00:02:58,569 It's a not, it's not a new one, but, it's about place where I'm working and living at the moment, about Crete, the Southwest part of Greece in Europe, an island. 37 00:02:59,075 --> 00:03:04,215 Uh, so the book is, uh, is named Island from Victoria Hislop. 38 00:03:04,234 --> 00:03:19,375 I don't know if you have read it or not and it deals with a small place, very small, um, even smaller from Crete island, um, next to Crete where people with Hansen's disease were kept a century ago. 39 00:03:19,894 --> 00:03:22,615 So if you haven't read the book, you should do it. 40 00:03:22,825 --> 00:03:24,025 It's a very interesting. 41 00:03:24,894 --> 00:03:25,315 Sara Dong: Great. 42 00:03:25,375 --> 00:03:26,095 Excellent. 43 00:03:26,185 --> 00:03:27,924 Well, thank you both for sharing. 44 00:03:28,195 --> 00:03:34,825 So moving us forward, today's consult question is about a mom and baby pair who have both become acutely ill. 45 00:03:35,275 --> 00:03:37,285 So I hand it over to Sarah, take it away 46 00:03:37,734 --> 00:03:39,144 Sarah May Johnson: On with the next consult. 47 00:03:39,565 --> 00:03:49,465 After a busy day on the ward, you're called by your obstetrics colleagues from the hospital across town about a curious conundrum that they have been dealing with in conjunction with neonatal colleagues at the hospital. 48 00:03:50,035 --> 00:03:54,145 The case involves a mother and neonatal pair whom are both fall acutely ill. 49 00:03:54,864 --> 00:04:07,464 The baby boy is born approximately 24 hours back to 32 year old, gravida one para zero mom who has become acutely unwell with peripartum fever and gastrointestinal symptoms. 50 00:04:07,885 --> 00:04:11,935 She has prominent abdominal pain and blood stricken loose stools. 51 00:04:12,325 --> 00:04:14,604 The antepartum course was otherwise uneventful. 52 00:04:15,654 --> 00:04:25,585 The baby was born at 39+4 weeks without any initial concerns, although since fallen ill with fever and suspicion for sepsis and has been transferred to NICU for ongoing care. 53 00:04:26,664 --> 00:04:30,414 The mother has also been transferred to ICU due to suspicion of sepsis. 54 00:04:30,835 --> 00:04:34,224 The mother was previously healthy with no significant past medical history. 55 00:04:34,674 --> 00:04:38,065 She was born in the Philippines, but has been living in the UK for four years. 56 00:04:38,664 --> 00:04:44,034 Booking bloods verbally reported to you over the phone are negative for hepatitis B, HIV, and syphilis. 57 00:04:44,534 --> 00:04:56,255 The baby is started on ben pen (benzylpenicillin) and amikacin, and acyclovir after blood cultures, full blood count, and biochemistry is drawn as per standard neonatal sepsis guidelines in the hospital. 58 00:04:57,085 --> 00:05:04,900 Mother is also started on broad spectrum antibiotics, ceftriaxone, gentamycin, and metronidazole after blood cultures are drawn. 59 00:05:05,590 --> 00:05:12,130 With a differential diagnosis remaining broad, what additional information would you like to gather on the phone? 60 00:05:12,580 --> 00:05:15,430 Would you have done anything different in the management of this child so far? 61 00:05:16,435 --> 00:05:19,205 Fani Ladomenou: There are some questions that I would like to ask on the phone. 62 00:05:19,805 --> 00:05:24,865 Uh, I was wondering whether the baby was born by cesarean section or by normal vaginal delivery. 63 00:05:25,645 --> 00:05:31,015 In case he was born by cesarean section, or was there a rupture of membranes before the section? 64 00:05:31,575 --> 00:05:34,845 Was this mother screened for group B strep during pregnancy? 65 00:05:35,445 --> 00:05:41,015 And did she also receive any intrapartum antibiotics in view of the fact that she was Febrile in labor? 66 00:05:41,205 --> 00:05:42,685 She was acutely unwell.. 67 00:05:43,425 --> 00:05:48,125 Uh, did the baby have any lumbar puncture or was he very unstable to have that? 68 00:05:48,645 --> 00:05:58,965 And I was also wondering whether the baby had any skin lesions suggestible of HSV infection or whether the mother had any history of orolabial HSV or any genital herpes. 69 00:05:59,715 --> 00:06:11,995 Did this baby having a stigma about other congenital infections, or clinical dissemination, such as for petechiae, blueberry muffin, hepatosplenomegaly, microcephaly, or any other rashes. 70 00:06:12,585 --> 00:06:18,255 And moreover, I would also like to know the results for the full blood count and the biochemistry. 71 00:06:18,585 --> 00:06:25,395 Did the full blood count show any disorders in cell counts or any cytopenias, or were there any abnormal liver function tests. 72 00:06:25,445 --> 00:06:29,375 And regarding the maternal history would also like to have some more information. 73 00:06:29,595 --> 00:06:33,755 Was this mother monogamous or was she having a high risk sexual behavior? 74 00:06:34,505 --> 00:06:38,855 Uh, for example, during pregnancy, was she consuming sushi or rare or raw meat? 75 00:06:38,915 --> 00:06:41,755 Was she consuming unpasteurized milk or cheese? 76 00:06:42,505 --> 00:06:45,005 And did she have any known sick contacts recently? 77 00:06:45,145 --> 00:06:49,695 For example, somebody with tuberculosis or did you have any recent exposure to animals? 78 00:06:50,265 --> 00:06:52,885 These are all the things that they would like to know before going ahead. 79 00:06:52,885 --> 00:06:55,665 At the moment I wouldn't have done anything differently. 80 00:06:55,875 --> 00:07:01,695 As we all know, sepsis is an important cause of morbidity and mortality among newborn infants. 81 00:07:01,935 --> 00:07:09,175 Here, although we still don't have the results of the blood culture back, we believe that we're dealing with an episode of early onset sepsis. 82 00:07:09,195 --> 00:07:13,305 And I'm saying early onset because the onset of symptoms occurred before seven days of age. 83 00:07:14,275 --> 00:07:24,215 This early onset infection is usually due to vertical transmission by ascending contaminated amniotic fluid or during the general delivery from bacteria in the mother's lower genital track. 84 00:07:25,145 --> 00:07:27,475 I mentioned in the questions group B Strep. 85 00:07:27,795 --> 00:07:35,135 Group B strep and E.coli are the most common bacteria, the most common causes of both early and late onset sepsis. 86 00:07:35,705 --> 00:07:41,495 Therefore the empiric antibiotic regimen would include agents active against these pathogens. 87 00:07:42,490 --> 00:08:01,900 Some other less common pathogens include Enterobacter, Enterococcus, Klebsiella, Listeria, Haemophilus influenza, other enteric gram-negative bacilli, Staph aureus, viridans streptococci, so the combination of ampicillin and gentamycin provide empiric coverage for these organisms until the culture results are available. 88 00:08:02,760 --> 00:08:09,910 In our practice, where I'm working in Greece at the moment, we're using ampicillin and gentamicin for early onset sepsis. 89 00:08:10,720 --> 00:08:17,040 If we consider central nervous system infection involvement, we add cefotaxime, a third generation cephalosporin. 90 00:08:17,480 --> 00:08:23,520 In cases we believe that we are dealing with nosocomial infection, which is not the case here, we use meropenem as empiric treatment. 91 00:08:24,405 --> 00:08:25,994 That's for early-onset sepsis. 92 00:08:26,055 --> 00:08:37,325 For late onset sepsis with onset after seven days of life, we use ampicillin and gentamycin or ampicillin and an extended spectrum cephalosporin, like cefotaxime or ceftazidime. 93 00:08:37,655 --> 00:08:41,865 Regarding now, the group B strep screening that I asked earlier during pregnancy. 94 00:08:42,255 --> 00:08:44,585 There are different guidelines in different countries. 95 00:08:45,135 --> 00:09:02,235 Um, regarding the United Kingdom where this baby was born, the Royal College of Obstetricians and Gynecologists doesn't recommend routine screening or testing for GBS colonization with pregnant women, because the clinical and cost effectiveness of this strategy remains unclear. 96 00:09:02,685 --> 00:09:06,745 Uh, therefore I wouldn't expect that this mother was screened during pregnancy. 97 00:09:07,255 --> 00:09:11,905 In Greece, where I'm working, although it's recommended by the national guidelines. 98 00:09:11,935 --> 00:09:14,935 In practice, it is rarely performed by the gynecologist. 99 00:09:15,385 --> 00:09:24,814 The national guidelines in Greece suggest that all pregnant women should be screened for grp B Strep by vaginal and rectal swab between 36 and 38 weeks of pregnancy. 100 00:09:25,505 --> 00:09:34,464 And those found be colonized should receive intrapartum antibiotics in case of a normal vaginal delivery or a Cesarian section with rupture of membranes. 101 00:09:35,074 --> 00:09:39,710 In the mother in our case, probably she wasn't screened but she was febrile in labor. 102 00:09:39,950 --> 00:09:43,730 So I would expect that she was covered within the intrapartum antibiotics. 103 00:09:43,790 --> 00:09:47,310 And the recommended antibiotic regime is ampicillin or penicillin. 104 00:09:48,875 --> 00:09:53,275 This patient has several key features that are consistent with listeria infection. 105 00:09:53,905 --> 00:10:03,415 In an immunocompetent host, injection of food contaminated with Listeria, that's why I asked about unpasteurized milk or cheese, or raw meat. 106 00:10:03,824 --> 00:10:08,484 Typically results in a symptomatic infection or mild febrile gastroenteritis. 107 00:10:09,095 --> 00:10:14,705 However, this mother is at increased risk for, for invasive Listeria infection because she's pregnant. 108 00:10:15,425 --> 00:10:24,945 Moreover, we know that the risk of symptomatic Listeria infection increases over the course of pregnancy, which makes such an infection quite likely in the end of pregnancy like in this case. 109 00:10:26,095 --> 00:10:34,265 Listeria infection in general is usually mild in pregnancy . More or less approximately two thirds of pregnant women with Listeria infection have symptoms. 110 00:10:34,805 --> 00:10:43,185 The most common of these symptoms are fever, influenza like illness, uh, some abdominal pain, headache and vomiting or diarrhea as in our case. 111 00:10:45,115 --> 00:10:51,645 Apart from the bacterial p athogens, we should also consider common nonbacterial agents associated with neonatal sepsis. 112 00:10:52,514 --> 00:10:58,684 These pathogens include herpes simplex virus (HSV), Enterovirus, Parechovirus, or Candida. 113 00:11:00,014 --> 00:11:04,924 I understand that this baby was empirically started on acyclovir for possible HSV infection. 114 00:11:05,834 --> 00:11:14,484 However, my thoughts are that the HSV infection rarely leads to diarrhea and would be unlikely to cause occur in the absence of a rash. 115 00:11:16,024 --> 00:11:20,864 In generally in the absence of skin issues, the diagnosis of neonatal HSV is quite challenging. 116 00:11:22,214 --> 00:11:33,974 In my practice in Greece, we don't usually cover early neonatal sepsis with acyclovir unless there is evidence suggestive of HSV infection, either from the clinical examination or from the history. 117 00:11:34,394 --> 00:11:45,164 For example, when we're dealing with the neonatal sepsis-like syndrome and vesicular lesions or sepsis like syndrome born to mother with active genital HSV lesions or any history of HSV infection. 118 00:11:46,124 --> 00:11:48,194 So these are my thoughts for now, Sarah. 119 00:11:50,054 --> 00:11:51,104 Sarah May Johnson: Thank you so much. 120 00:11:51,104 --> 00:11:56,174 That was an interesting overview and also nice to touch base on different practices that we see in different countries. 121 00:11:56,894 --> 00:12:00,524 The next day you are called by our neonatal colleagues from the same hospital. 122 00:12:00,824 --> 00:12:04,034 Uh, you spoke to yesterday with an update on the baby status. 123 00:12:04,394 --> 00:12:05,984 Unfortunately, things have deteriorated. 124 00:12:06,779 --> 00:12:11,189 Baby has been started on dopamine for hypotension, and is now intubated and ventilated. 125 00:12:11,729 --> 00:12:18,779 A 15 minute generalized tonic clonic seizure occurred overnight requiring phenobarbital administration. 126 00:12:19,379 --> 00:12:20,819 Mom's condition is stable. 127 00:12:20,889 --> 00:12:27,119 She remains in the ICU with ongoing gastrointestinal symptoms and imaging findings consistent with frank colitis. 128 00:12:27,749 --> 00:12:42,929 The baby's blood work demonstrates profound liver and kidney injury with an ALT 2,156 units per liter, deranged coagulation, INR of 2.9, requiring administration of FFP and vitamin K. 129 00:12:44,059 --> 00:12:47,400 Creatinine is raised measuring 313 mmol/L. 130 00:12:48,809 --> 00:12:57,379 The full blood count demonstrates an HB of 117 grams per liter and a platelet count of 14 requiring a platelet transfusion overnight. 131 00:12:58,169 --> 00:13:06,254 Full blood count measures, white blood cell count measures 2.1 with an ANC of 1.3 and ALC of 0.7. 132 00:13:06,854 --> 00:13:09,494 The CRP measures 15 milligrams per liter. 133 00:13:10,784 --> 00:13:19,675 The overnight junior doctor noted two small vesicular lesions on the left lower leg, which was swapped for CNS and HSV PCR. 134 00:13:20,334 --> 00:13:22,704 A blood HSV PCR was also obtained. 135 00:13:23,064 --> 00:13:25,905 An LP was deemed unsafe due to their coagulopathy. 136 00:13:26,545 --> 00:13:30,834 In discussion with pharmacy, all medications were adjusted renal clearance. 137 00:13:31,194 --> 00:13:38,004 This morning, the neonatal team were made aware that mum's HSV blood PCR and PCR for stool both returned positive. 138 00:13:38,874 --> 00:13:40,655 She's also been started on acyclovir. 139 00:13:41,530 --> 00:13:44,589 With this in mind, further exposure history was gathered. 140 00:13:45,310 --> 00:13:49,449 The mother has no history of oral labial HSV, or genital herpes. 141 00:13:49,630 --> 00:13:52,540 The father does get recurrent orolabial herpes. 142 00:13:52,540 --> 00:13:57,849 And in fact has a noticeable ulcerating lesion on his upper lip when further history is obtained. 143 00:13:58,630 --> 00:14:00,520 There is no history of genital herpes. 144 00:14:00,849 --> 00:14:10,420 There is a history of orovaginal contact approximately four days prior to delivery, two days after which the father developed the painful ulcerating lesion on his lip. 145 00:14:11,209 --> 00:14:18,790 Can you discuss the approach to management of neonatal HSV, and would you make any changes to the management at this point? 146 00:14:21,630 --> 00:14:22,260 Fani Ladomenou: Interesting. 147 00:14:23,370 --> 00:14:33,700 It's obvious now that we are dealing with a disseminated neonatal HSV infection, despite the fact that the initial history of maternal colitis was not suggestive of such an infection. 148 00:14:34,810 --> 00:14:46,560 Herpes simplex should be considered, as mentioned before, as a causative agent in neonates with fever, especially within the first few days of life, a vesicular rash, or abnormal sense of findings. 149 00:14:46,590 --> 00:14:50,790 We didn't have an LP, of course, in this case, especially in the presence of seizures. 150 00:14:51,760 --> 00:14:59,190 Neonatal herpetic infections often are severe with high mortality and morbidity, even when antiviral therapies are administered. 151 00:15:00,350 --> 00:15:13,080 The risk of transmission of HSV to the neonate remain significantly higher with primary maternal infectious acquired closer to the time of delivery, as it obviously happened in our case, compared with recurrent infections. 152 00:15:13,170 --> 00:15:19,950 The percentage, for example, is 50 to 60% with primary infections versus less than 3% for recurrent infection. 153 00:15:21,015 --> 00:15:29,195 Of course, distinguishing between primary and recurrent HSV infections in women by history and the clinical examination, may be impossible. 154 00:15:30,005 --> 00:15:32,315 Maternal type specific serology may be useful. 155 00:15:33,635 --> 00:15:44,155 More than 75% of infants with HSV infection have been born to women with no history or clinical findings, suggestive of active HSV infection during pregnancy. 156 00:15:45,270 --> 00:15:53,040 Regarding now treatment, intravenous acyclovir should be administered at the time of, the diagnosis of HSV is suspected. 157 00:15:54,330 --> 00:15:58,290 It has been described the prompt administration improves outcome. 158 00:15:58,830 --> 00:16:03,610 Of course, there is no place for oral acyclovir in neonatal treatment of acute HSV. 159 00:16:04,510 --> 00:16:11,100 The dose of acyclovir of all forms of neonatal HSV is 60 mg/kg/d, intravenously, divided every eight hours. 160 00:16:12,450 --> 00:16:17,760 The dose of acyclovir must be adjusted to neonates with renal impairment, as in the case of this baby. 161 00:16:18,350 --> 00:16:34,560 The indications for acyclovir therapy include virologically proven HSV disease, clinically suspected HSV disease pending viral studies, asymptomatic but at risk due to exposure, uh, from some of those maternal active genital lesions. 162 00:16:35,980 --> 00:16:39,430 The indications for empiric acyclovir are not standardized. 163 00:16:39,765 --> 00:16:46,885 Uh, most of the experts agree empiric acyclovir is indicated for neonates with clinical features suggestive of HSV infection. 164 00:16:47,415 --> 00:17:06,405 And these features include mucocutaneous vesicles, seizures, lethargy, respiratory distress, thrombocytopenia, coagulopathy, blood losing from intravascular catheter size, hypothermia, sepsis like illness, hepatomegaly, ascites, or even markedly elevated transaminases. 165 00:17:07,204 --> 00:17:15,300 Many experts recommend empiric treatment for ill appearing neonates with fever or aseptic meningitis until results of HSV workup are known. 166 00:17:16,190 --> 00:17:19,490 This is probably what they follow in the UK, where the baby was born. 167 00:17:20,390 --> 00:17:22,740 That's why they started acyclovir from the very beginning. 168 00:17:23,554 --> 00:17:40,905 However, uh, expert opinions differ regarding the relative benefits, risk, and cost-effective, effectiveness of empiric acyclovir before virological confirmation in other clinical situations, such as when we have a CSF pleiocytosis with, uh, a predominance of mononuclear cells in an otherwise well-appearing infant. 169 00:17:41,345 --> 00:17:51,755 When we have persistent or recurrent erythema or crusting at the site of a scalp electrode, or when we have fever without localizing signs and the neonate is less than 21 days of age. 170 00:17:53,715 --> 00:18:09,280 Now neonatal HSV is classified into three main categories for therapeutic and diagnostic considerations-- localized skin, eye and mouth disease; CNS with or without localized disease; and disseminated disease. 171 00:18:10,900 --> 00:18:16,910 Approximately one out of four cases of neonatal HSV manifest as disseminated disease. 172 00:18:17,530 --> 00:18:23,345 30% as CNS disease, and 45% manifest as skin, mouth and eye localized disease. 173 00:18:23,795 --> 00:18:38,515 Of course, there is some overlap in these categories, for instance, approximately two thirds of the neonates with disseminated or CNS disease have skin lesions, but these lesions may not be present at the time of onset of symptoms as in the baby in our case. 174 00:18:39,635 --> 00:18:46,545 The duration now of acyclovir therapy for neonatal infection depends upon the pattern of illness and response to therapy. 175 00:18:47,525 --> 00:18:54,515 We treat localized disease with a minimum of 14 days if disseminated and CNS disease have been excluded. 176 00:18:55,265 --> 00:19:00,575 And disseminated and CNS disease should be treated for a minimum of 21 days. 177 00:19:01,445 --> 00:19:11,725 Because the presence of HSV DNA in the CSF is associated, of course, with poor outcome, lumbar puncture should be repeated near the end of the therapy to ensure that CSF HSV PCR is negative. 178 00:19:13,054 --> 00:19:21,925 For those infants with persistently positive CSF HSV PCR despite 21 days of acyclovir therapy, antiviral treatment should be continued. 179 00:19:22,075 --> 00:19:25,865 And HSV CSF PCR testing should be repeated weekly until negative. 180 00:19:26,875 --> 00:19:36,485 Thus the baby in our case that was diagnosed with disseminated disease should receive at least 21 days of her IV acyclovir at the proper dose, as mentioned before. 181 00:19:37,095 --> 00:19:43,605 And in this case we don't know if there is CNS involvement, as we didn't have an LP, but, uh, probably there is. 182 00:19:45,105 --> 00:19:54,795 Even though this baby was stable enough, when we suspect HSV, we should have received a comprehensive laboratory evaluation for HSV before initiation of acyclovir therapy. 183 00:19:55,660 --> 00:20:07,890 And this workup should include testing to detect HSV including surface HSV cultures or HSV PCR from the conjunctivae, eye, mouth, nasopharynx, and rectum. 184 00:20:08,240 --> 00:20:16,690 This would also consist of HSV culture or HSV PCR of swabs, scraping some skin and mucous membrane lesions if present, in our case, we have. 185 00:20:17,500 --> 00:20:24,520 CSF HSV PCR, of course, the baby was not safe enough to have one, uh, to have an LP. 186 00:20:24,960 --> 00:20:32,020 Whole blood and plasma HSV PCR and a viral culture or HSV PCR of other specimens that would be available. 187 00:20:32,020 --> 00:20:33,590 For example, tracheal aspirates. 188 00:20:34,990 --> 00:20:46,780 They should also be testing to determine the degree of organ involvement and studies to exclude other diseases that may cause similar symptoms, so we need full blood count, including differential and platelet count. 189 00:20:46,810 --> 00:20:51,190 We need liver transaminases, total and direct bilirubin, ammonia. 190 00:20:51,910 --> 00:21:01,100 Uh, just to point out here that the ammonia should be performed to exclude liver disease and metabolic disease in neonates with elevated liver enzymes and fulminant sepsis. 191 00:21:01,780 --> 00:21:05,420 Um, but it's not necessarily for all of neonates with suspected HSV. 192 00:21:06,020 --> 00:21:27,340 We also need blood urea, creatinine, and urinalysis; CSF cell count and differential, CSF glucose and protein, eye examination, neuro imaging, EEG in neonates suspected to have CNS disease, and chest radiograph for neonates with respiratory distress and blood and CSF cultures, of course, to evaluate for bacterial sepsis. 193 00:21:28,510 --> 00:21:31,570 So, Sarah, this is what I'm thinking at the moment for this baby. 194 00:21:31,570 --> 00:21:39,555 Sarah May Johnson: Hm I totally hear all of that, and it's so interesting to think that, of course, the diagnosis is in the history. 195 00:21:39,885 --> 00:21:47,055 Although we so infrequently ask about HSV in pregnancy histories and of the parents that we see until they're symptomatic. 196 00:21:48,045 --> 00:21:53,505 In follow up with the local team two days afterwards, things again, seem to be going in the wrong direction. 197 00:21:54,370 --> 00:21:59,170 The coagulopathy and thrombocytopenia are persistent requiring additional blood products. 198 00:21:59,830 --> 00:22:08,470 The liver function has worsened with an INR 3.7 and the ALT continues to rise and is now 3098 units per liter. 199 00:22:09,310 --> 00:22:16,470 The creatinine remains elevated 329 mmol/L, which is 3.72 mg/dL. 200 00:22:17,210 --> 00:22:22,370 The babies respiratory status has also deteriorated requiring escalation to jet ventilation. 201 00:22:22,760 --> 00:22:27,370 And as such, the decision has been made to transfer the baby to a higher level of NICU at your hospital. 202 00:22:28,280 --> 00:22:33,660 In-house blood HSV PCR is positive at a high copies/ml value. 203 00:22:34,390 --> 00:22:42,970 Six days into the baby's stay in your hospital while still on acyclovir, HSV PCR remains positive without any decline in the quantitative value. 204 00:22:43,750 --> 00:22:48,370 As a result, foscarnet is added to the acyclovir treatment at renal adjusted doses. 205 00:22:49,080 --> 00:22:55,810 Can you comment on dual therapy for persistent viremia , and any thoughts on the management? 206 00:22:56,690 --> 00:23:04,490 Fani Ladomenou: Well, it seems that here we have an unusual scenario with a patient not responding to treatment despite being on IV acyclovir for six days. 207 00:23:05,240 --> 00:23:10,820 And it seems like HSV PCR remains positive with no decline in the quantitative value. 208 00:23:12,180 --> 00:23:22,620 My thoughts around this failure is first of all, we may have a potential underlying immune deficiency or possibly there's HSV resistance to acyclovir. 209 00:23:23,530 --> 00:23:40,530 Regarding the immunodeficiency, there is a number of inborn errors associated with susceptibility to HSV such as a severe combined immune deficiency, GATA2 deficiency, DOCK8 deficiency, interleukin 12 receptor deficiency or IFN-gamma receptor deficiency and so on. 210 00:23:41,165 --> 00:23:54,485 However, even in the case we have here, in immunodeficiency in a baby being so acutely unwell, um, we possibly couldn't go for immunological tests because they would be unreliable at this stage. 211 00:23:55,815 --> 00:24:13,330 Regarding my thoughts on HSV resistance to acyclovir, neonatal HSV infections are assumed to result usually from susceptible virus, because it most often follow unappreciated, primary maternal infection, as in our case, or unappreciated reactivation in mothers with prior infection. 212 00:24:13,900 --> 00:24:19,540 In either instance, the likelihood of transmitting acyclovir resistant HSV is very low. 213 00:24:20,715 --> 00:24:29,345 In the first situation, unrecognized maternal infection would be anticipated and maternal HSV wouldn't be exposed to the selective pressure of acyclovir. 214 00:24:30,075 --> 00:24:33,695 When it's due to reactivation, the frequency of resistant HSV is very, very low. 215 00:24:34,845 --> 00:24:50,149 Obviously the mother in our case had no prior history of genital HSV or acyclovir treatment, despite that, uh, I would suggest HSV isolates should be studied for antiviral susceptibility by enzyme immunoassay measuring antigen reduction. 216 00:24:50,825 --> 00:24:54,315 Then they could continue dual therapy with the acyclovir and foscarnet. 217 00:24:54,895 --> 00:24:56,125 Sarah May Johnson: All very good points. 218 00:24:56,845 --> 00:25:10,685 10 days into admission at the transferring hospital with further deterioration in ICU, the difficult decision was made by the parents and the medical team to take a comfort care approach, and the baby passed away in the parents' arms. 219 00:25:10,825 --> 00:25:17,635 After 12 days of antiviral therapy, the blood PCR quantitative viral load remained unchanged. 220 00:25:18,415 --> 00:25:23,725 Retrospective resistance testing did not reveal any acyclovir resistant mutations. 221 00:25:24,505 --> 00:25:30,325 Are there any additional pearls about the case or clinical pearls regarding HSV in the neonatal period? 222 00:25:32,535 --> 00:25:33,775 Fani Ladomenou: Unfortunately. 223 00:25:35,185 --> 00:25:39,805 Neonatal HSV is a serious infection, as I mentioned earlier, with high morbidity and mortality. 224 00:25:40,465 --> 00:25:44,805 Even in cases with prompt treatment with IV acyclovir as in this baby. 225 00:25:45,865 --> 00:25:56,795 Uh, it has been noticed that the one year mortality rate for disseminated diseases is 29%, which means one out of three babies will die even if they get the proper treatment. 226 00:25:56,825 --> 00:26:09,445 The risk of mortality is increased in infants with lethargy, severe hepatitis, acute liver failure, pneumonia, at the time of presentation, disseminated, vascular coagulopathy, prematurity, pneumonitis. 227 00:26:09,715 --> 00:26:16,735 It is important to remember that HSV infection is lifelong, even with the appropriate therapy. 228 00:26:17,425 --> 00:26:25,355 Even in those neonates that survive, recurrence of mucocutaneous lesions, eye disease, or even CNS disease may occur. 229 00:26:26,475 --> 00:26:41,280 Following for entire treatment for all forms of neonatal HSV in that form and the doses that we mentioned earlier, we suggest suppressive therapy with oral acyclovir 300 milligram per meter squared per dose two times per day for six months. 230 00:26:41,940 --> 00:26:45,490 Of course the dose should be adjusted each month to account for growth. 231 00:26:46,910 --> 00:26:58,680 Uh, these recommendation I mentioned is based on a randomized clinical trial in which suppressive therapy reduced cutaneous recurrences and was associated with the improved neurological outcomes in infants with CNS disease. 232 00:26:59,970 --> 00:27:06,950 Moreover if HSV eye disease is present, many experts suggest also pushing for up to one year, not just six months. 233 00:27:09,000 --> 00:27:49,650 In case now of recurrences, uh, even when on suppression therapy, the ultimate optimal management of cutaneous recurrence is not established, however, uh, treatment doses of oral acyclovir, 10-20 mg/kg/dose two times per day for young infants, or 10 to 15 mg/kg/dose four to five times a day for older infants and children, may be administered early at the time of each recurrence to reduce discomfort and shedding associated with these lesions, or preemptively for a brief period for one or two weeks when a cutaneous recurrence is anticipated, which is quite usual at times of high stress or exposure to sunlight. 234 00:27:50,970 --> 00:28:00,070 When patients have frequent cutaneous recurrences that are painful or cause disturbance in daily life, long term oral suppression may be of benefit. 235 00:28:02,645 --> 00:28:09,425 These are my thoughts, Sarah, for this case, very interesting case, unfortunately, with not a very good course. 236 00:28:10,115 --> 00:28:10,475 Sara Dong: Yeah. 237 00:28:11,225 --> 00:28:30,410 I think one thing that is interesting, we didn't really talk about it as much because our goal was to focus on baby, but it sounds like mom was quite ill and I think it's a good reminder that mothers can have really fulminant hepatitis from HSV in pregnancy and have pretty high morbidity and mortality. 238 00:28:30,760 --> 00:28:45,700 So I think it was, this is really nice because we talked through baby, but also just taking a big picture step back, I think thinking about the mom who didn't necessarily have lesions, but clearly it was unwell is also a good, good thing to remember 239 00:28:45,750 --> 00:28:48,730 Fani Ladomenou: Obviously her colitis was a bit misleading. 240 00:28:49,060 --> 00:28:55,685 That's why it was more consistent with Listeria, something similar, and not HSV. 241 00:28:56,495 --> 00:28:57,835 Sara Dong: Well that does it for today. 242 00:28:57,865 --> 00:29:01,015 Thank you so much to Sarah and Fani for joining us. 243 00:29:01,960 --> 00:29:02,570 Fani Ladomenou: Thank you, Sara. 244 00:29:02,590 --> 00:29:02,860 Thank you. 245 00:29:03,790 --> 00:29:04,720 Sarah May Johnson: Thank you. 246 00:29:04,810 --> 00:29:05,500 Thank you. 247 00:29:06,370 --> 00:29:12,640 Sara Dong: If you haven't already, please make sure to check out the other episodes from the rest of our Curious Congenital Conundrum series. 248 00:29:13,090 --> 00:29:23,620 I'll just mention our quick usual disclaimer, that all presented patients on this podcast are inspired by patient experiences, but cases are constructed or significantly altered and de-identified for learning purposes. 249 00:29:25,150 --> 00:29:38,290 If you haven't checked it out or are new to Febrile, please visit our website, febrilepodcast.com for more information, and to find the Consult Notes, which are written complements to the show with links to references as well as the library of ID infographics. 250 00:29:38,800 --> 00:29:39,730 Thanks for listening. 251 00:29:39,730 --> 00:29:41,650 Stay safe and I'll see you next time.