1 00:00:08,640 --> 00:00:09,510 Sara Dong: Hi, everyone. 2 00:00:09,510 --> 00:00:14,220 Welcome to Febrile, a cultured podcast about all things infectious disease. 3 00:00:14,340 --> 00:00:20,190 We use consult questions to dive into ID clinical reasoning, diagnostics, and antimicrobial management. 4 00:00:20,760 --> 00:00:23,640 I'm Sara Dong, your host and a Med-Peds ID fellow. 5 00:00:23,790 --> 00:00:29,220 Here on Febrile, we use patient cases and chat with ID discussants to learn more about high yield topics. 6 00:00:29,895 --> 00:00:32,144 Our co-host today is Dr. 7 00:00:32,144 --> 00:00:33,765 Pratik "Tik" Patel. 8 00:00:33,915 --> 00:00:39,105 He is a second year pediatric ID fellow at Emory University and Children's Healthcare of Atlanta. 9 00:00:39,615 --> 00:00:53,715 He also completed a Pediatric Hematology Oncology fellowship, also at Emory, and wishes to leverage his training in both fields to advance the ID care of immunocompromised children with a focus on those undergoing treatment of cancer and stem cell transplant. 10 00:00:54,099 --> 00:01:00,790 He also has a research interest in introduction and implementation of novel diagnostics for improved stewardship and clinical care. 11 00:01:01,059 --> 00:01:01,569 Tik Patel: Hey everyone. 12 00:01:01,839 --> 00:01:03,580 Sara Dong: Our discussant today is Dr. 13 00:01:03,580 --> 00:01:04,330 Joshua Wolf. 14 00:01:04,539 --> 00:01:07,479 Josh is a Pediatric Infectious Disease physician at St. 15 00:01:07,485 --> 00:01:17,039 Jude Children's Research Hospital, where he is the Division Director for Hematology and Oncology Infectious Diseases and Medical Director of Antimicrobial Stewardship. 16 00:01:17,384 --> 00:01:27,914 He is an Associate Professor at the University of Tennessee Health Science Center, and he trained at the Royal Children's Hospital and Peter McCollum Cancer Center in Melbourne, Australia and St. 17 00:01:27,914 --> 00:01:31,155 Jude and Le Bonheur Children's Hospital in Memphis, Tennessee. 18 00:01:31,425 --> 00:01:41,265 His research interest is focused on novel approaches to prediction, prevention, and amelioration of life threatening infections in children with cancer. 19 00:01:41,595 --> 00:01:42,135 Josh Wolf: Hi. 20 00:01:42,585 --> 00:01:43,005 Sara Dong: All right. 21 00:01:43,035 --> 00:01:44,475 I'm so glad you guys are here. 22 00:01:44,535 --> 00:01:49,155 Before we get to the case, we always ask one question, uh, meant to be non-medical. 23 00:01:49,185 --> 00:01:57,415 As everyone's favorite cultured podcast, I'd love to hear if you guys have any pieces of culture or things that you have enjoyed recently that you wanna share with the listeners. 24 00:01:57,630 --> 00:01:58,800 Tik Patel: Sure I can go first. 25 00:01:58,830 --> 00:02:01,140 Um, I enjoy travel hacking. 26 00:02:01,350 --> 00:02:05,220 Uh, so this stems from a passion of mine, which is I love to travel. 27 00:02:05,520 --> 00:02:12,750 Um, but I don't like to spend a lot of money . So with travel hacking, I use credit cards to maximize, uh, points and miles. 28 00:02:12,750 --> 00:02:13,490 So I travel on the cheap. 29 00:02:14,400 --> 00:02:21,360 Uh, I've churned, an official travel hacking term, through over 30 credit cards and been to over 30 countries. 30 00:02:21,390 --> 00:02:21,450 Sara Dong: Wow. 31 00:02:21,540 --> 00:02:23,490 Tik Patel: So I'm always plotting out my next trip. 32 00:02:23,580 --> 00:02:27,090 Sara Dong: Oh, so this is not like a casual, like you're serious travel hacker. 33 00:02:28,140 --> 00:02:28,410 Tik Patel: yep. 34 00:02:29,340 --> 00:02:30,270 As much as one can be. 35 00:02:30,275 --> 00:02:30,330 Yeah. 36 00:02:31,830 --> 00:02:32,640 Sara Dong: What about you, Josh? 37 00:02:32,880 --> 00:02:38,490 Josh Wolf: Uh, mine couldn't be any more different and I have a seven month old daughter. 38 00:02:38,550 --> 00:02:49,155 And so I'm really into a book at the moment called, That's Not My Squirrel , which is a touchy feely board book. 39 00:02:49,995 --> 00:02:50,985 Sara Dong: Great, great. 40 00:02:52,455 --> 00:02:54,105 well, it's very pediatric appropriate. 41 00:02:54,495 --> 00:02:56,325 So today's consult question. 42 00:02:56,595 --> 00:03:04,575 Um, you get a call about a teenage boy undergoing treatment for cancer with respiratory distress, who unfortunately has been admitted to the ICU overnight. 43 00:03:04,575 --> 00:03:07,665 Can you please assist with evaluation and antibiotics? 44 00:03:08,265 --> 00:03:09,055 So I'll hand it over. 45 00:03:09,685 --> 00:03:17,890 Tik Patel: So we have a 17 year old male, uh, who has a history of a relapsed/ refractory brain tumor who came to the ED with three days of tachypnea and hypoxia. 46 00:03:17,890 --> 00:03:20,400 It started as a sore throat five days ago, 47 00:03:20,760 --> 00:03:27,540 and then seen, was a, was seen at the PCPs office at which time a rapid flu, COVID, Strep tests were negative. 48 00:03:28,530 --> 00:03:32,910 Unfortunately, continued to feel bad with tachypnea, mild sputum production. 49 00:03:33,060 --> 00:03:39,885 And so his mother used a home O2 pulse ox, and noticed he was saturating 87 to 89% on room air. 50 00:03:40,575 --> 00:03:41,175 So came. 51 00:03:41,175 --> 00:03:42,435 So he came to the ER. 52 00:03:43,575 --> 00:03:47,865 In the ER, he's a febrile, mildly tachycardic and hypotensive. 53 00:03:48,015 --> 00:03:57,465 And so was given a fluid bolus, had respiratory distress with tachypnea and accessory muscle usage and he was setting 75% on room air. 54 00:03:57,585 --> 00:04:03,795 So he was placed on high flow nasal cannula at 12 liters with an FiO2 of 40%. 55 00:04:05,070 --> 00:04:13,220 Chest x-ray was done, which showed bilateral patchy infiltrates and a respiratory viral panel was positive for rhinovirus. 56 00:04:14,340 --> 00:04:33,620 Upon other laboratory examinations, a complete blood count showed a white blood cell count of 3.8, a hemoglobin of 10 platelets of one 90, and a chemistry panel showed an elevated AST at 80, ALT of 45, normal bilirubin and normal renal function. 57 00:04:34,820 --> 00:04:41,895 Inflammatory markers were elevated with a CRP of 13 milligrams per deciliter, and an ESR of 81. 58 00:04:43,034 --> 00:04:45,284 And the patient did not have a central venous line. 59 00:04:45,465 --> 00:04:47,325 So peripheral blood culture was drawn. 60 00:04:48,255 --> 00:04:55,424 He was started on empiric antibiotics of piperacillin-tazobactam and azithromycin and admitted to the oncology floor. 61 00:04:56,685 --> 00:05:02,265 And very quickly on this first day of hospitalization, he became febrile, had worsening hypoxia. 62 00:05:02,325 --> 00:05:09,465 So he was transferred to the pediatric intensive care unit for BiPAP and infectious disease was consulted. 63 00:05:10,635 --> 00:05:16,965 So here we have an immunocompromised critically ill teenager in the ICU with fever and respiratory distress. 64 00:05:17,685 --> 00:05:22,545 What are you thinking, Josh, when you're scanning the chart before seeing the patient, what are you looking at? 65 00:05:22,545 --> 00:05:25,665 And what questions will you walk into the room already planning to ask. 66 00:05:26,295 --> 00:05:35,865 Josh Wolf: Thanks Tik so this is an immunocompromised adolescent with fever and acute respiratory failure following a sore throat, but immunocompromised ain't immunocompromised. 67 00:05:35,865 --> 00:05:45,865 And so, I wouldn't expect him to be uh, profoundly immunosuppressed as we'd see in a patient post hematopoietic stem cell transplant or intensive therapy for leukemia. 68 00:05:46,105 --> 00:05:50,305 And that does affect the differential, but different people respond differently to chemo. 69 00:05:50,305 --> 00:05:51,414 So I'll keep an open mind. 70 00:05:52,045 --> 00:05:59,835 Before I go in the room, I'll try and get a picture of his recent chemotherapy and review his blood count to get a feel for the depth and the characteristics of his immunosuppression. 71 00:06:01,050 --> 00:06:05,790 In terms of this possible differential diagnosis, it's in two groups, infectious or non infectious. 72 00:06:05,940 --> 00:06:08,909 And, um, the infectious differential here is quite broad. 73 00:06:09,300 --> 00:06:13,890 Uh, it can include viral, bacterial, fungal, or even parasitic infections. 74 00:06:13,895 --> 00:06:19,860 And it's important to consider the common causes of pneumo- pneumonitis or lower respiratory tract infection in any host. 75 00:06:20,280 --> 00:06:22,770 Um, and then some that are special for immunocompromised hosts. 76 00:06:22,770 --> 00:06:26,851 And in here, I'm thinking about respiratory viruses like RSV, adeno, 77 00:06:27,115 --> 00:06:37,405 parainfluenza, reactivation of herpes viruses like CMV or HSV, uh, bacterial pneumonia with pneumococcus, mycoplasma, Staph aureus, or even Pseudomonas if neutropenic. 78 00:06:37,915 --> 00:06:48,085 And then other bacteria like psittacosis, mycobacteria, uh, nocardia, legionella are all really rare in this setting, but with might consider them under certain circumstances. 79 00:06:48,385 --> 00:06:54,315 And then, um, locally here, fungi like Histoplasma and Blastomyces are considerations. 80 00:06:55,080 --> 00:06:59,310 And pneumocystic pneumonia needs to be on the, uh, on the differential. 81 00:06:59,900 --> 00:07:12,750 Other opportunistic fungi like disseminated candidiasis or aspergillosis would be less likely in this patient because of his degree of immunocompromise and then strongyloides or toxoplasma usually affect much more immunocompromised hosts. 82 00:07:12,960 --> 00:07:15,690 We've certainly seen other parasites like toxocara in this. 83 00:07:16,520 --> 00:07:25,920 And then on the non-infectious diseases side, things like chemotherapy side effects, like, uh, gemcitabine bleomycin methotrexate, usually not acute or febrile. 84 00:07:26,600 --> 00:07:33,290 And then there are other unusual things like vaping associated lung disease, um, which again, doesn't quite fit with the picture. 85 00:07:33,620 --> 00:07:40,420 And then lastly, and really importantly, I think it's difficult to pin this on a, a picorna RNA virus, like rhinovirus or enterovirus. 86 00:07:40,610 --> 00:07:43,250 That's a very rare cause of lower respiratory tract infection. 87 00:07:43,250 --> 00:07:44,790 And I keep looking. 88 00:07:45,530 --> 00:07:45,890 Tik Patel: great. 89 00:07:46,485 --> 00:07:47,595 Yeah, that's a great differential. 90 00:07:47,595 --> 00:08:01,005 So in terms of our exposure history, the patient was originally diagnosed with a brain tumor four years ago, and subsequently relapsed two years later, he was treated with surgery, radiation, and chemotherapy. 91 00:08:01,845 --> 00:08:05,505 He had progression a year af- a year prior to his presentation. 92 00:08:06,015 --> 00:08:12,275 And so now he's on a clinical trial with oral chemotherapy, which includes cyclophosphamide and etoposide. 93 00:08:13,515 --> 00:08:17,205 His vaccines are not up to date due to, uh, cancer therapy. 94 00:08:18,165 --> 00:08:24,045 He lives in the Southern United States with his parents and a brother who recently experienced gastroenteritis. 95 00:08:24,645 --> 00:08:31,545 He's had no recent travel due to social distancing in quarantine, but he has gone to Europe in the past and he has no pets. 96 00:08:32,325 --> 00:08:37,455 He has gone swimming at a local lake and there has been some recent remodeling of his household. 97 00:08:38,414 --> 00:08:43,544 As far as his labs, specifically, his absolute neutrophil count is 2,500. 98 00:08:44,535 --> 00:08:49,905 And in review of his previous records, he has not been neutropenic anytime in the last year. 99 00:08:51,195 --> 00:08:59,235 And then his absolute lymphocyte count is 300 and importantly, he has not been above 1000 in the last six months. 100 00:08:59,685 --> 00:09:08,400 He reports taking trimethoprim-sulfamethoxazole or Bactrim prophylaxis Saturday and Sunday without missed doses. 101 00:09:09,089 --> 00:09:11,370 And he's on no other infectious prophylaxis. 102 00:09:12,780 --> 00:09:19,349 So with this information, how does this change your differential and what recommendations will you make to the team about next steps in management? 103 00:09:20,130 --> 00:09:22,890 Josh Wolf: I presume that the rest of the exposure history is negative. 104 00:09:22,890 --> 00:09:27,420 I'd also be asking about hobbies, hunting, vaping, animal contact, other than pets. 105 00:09:27,569 --> 00:09:32,250 It's so amazing how often they, uh, swept outta chicken coop, but didn't mention it because they're not pets. 106 00:09:33,224 --> 00:09:35,265 Uh, if he's had raw milk, game meat. 107 00:09:35,685 --> 00:09:38,265 Um, so, so I'll take a full exposure history. 108 00:09:38,265 --> 00:09:42,495 It's really essential in a case like this, to make sure you're not missing something. 109 00:09:42,645 --> 00:09:45,135 And there are also a few exam findings I be interested in. 110 00:09:45,255 --> 00:09:46,785 Does he have lung crackles? 111 00:09:46,844 --> 00:09:58,200 Uh, does he have, whe the nature of these can sometimes help, like, fine crackles and paroxysmal coughing with deep inspiration, especially if it, they have desaturation might be more likely to be something like Pneumocystis.. 112 00:09:58,530 --> 00:10:02,220 Does he have neck tenderness to suggest jugular vein thrombosis? 113 00:10:02,220 --> 00:10:03,900 Does he have oral thrush or ulcerations? 114 00:10:04,140 --> 00:10:08,160 Those are all things that can give you clues to what's going on, uh, from the exam. 115 00:10:08,165 --> 00:10:14,985 And then living in the rural Southeast Eastern US is theoretically a risk factor for Strongyloides but it's very rare in my experience. 116 00:10:14,985 --> 00:10:19,065 And we wouldn't expect hyper infection syndrome in someone with his degree of immunocompromised. 117 00:10:19,395 --> 00:10:22,560 Um, And then he isn't neutropenic. 118 00:10:22,590 --> 00:10:32,460 And so that does, um, push me away from unusual bacterial infections, but the prolonged, uh, lymphopenia, even though it's not profound, does raise, uh, his risk. 119 00:10:32,550 --> 00:10:33,540 In HIV patients, 120 00:10:33,540 --> 00:10:39,290 we think about prophylaxis for pneumocystis below a CD4 count of about 200 and mycobacteria or CMV. 121 00:10:39,360 --> 00:10:40,860 Under CD4, kind of about 50. 122 00:10:41,130 --> 00:10:44,580 So is in that range of moderate T-cell or lymphocyte deficiency. 123 00:10:44,880 --> 00:10:47,060 And you might also have some antibody deficiency. 124 00:10:47,060 --> 00:10:51,350 See, this is really typical for solid tumor patients getting non-intensive chemotherapy. 125 00:10:51,800 --> 00:11:06,560 And so I put a, uh, him in this, uh, pure area of immunocompromised from the standpoint of lymphocyte deficiency, moderate, um, neutrophil and neutropenia doesn't seem to exist right now. 126 00:11:06,560 --> 00:11:09,440 And hasn't been in the recent past and antibody deficiency. 127 00:11:09,440 --> 00:11:16,305 He may have some degree of antibody deficiency and, my workup for him is gonna be pretty broad upfront. 128 00:11:16,305 --> 00:11:19,755 This kid is sick and getting sicker and, um, it's happening quickly. 129 00:11:19,905 --> 00:11:24,675 And so I'm thinking about respiratory viral, uh, panel, which I I think has already been done. 130 00:11:24,735 --> 00:11:30,105 And in this context, I'd send labs, Histoplasma, Blastomyces,, CMV, adenovirus. 131 00:11:30,255 --> 00:11:31,795 I'd love to see a chest CT. 132 00:11:32,175 --> 00:11:41,785 And this is one of the really rare times that I think about sending a beta-d-glucan test in general, BDG, is contraindicated in children for diagnosis of candidiasis 133 00:11:41,995 --> 00:11:47,695 or for diagnosis of other invasive fungal infection because of its very low positive and negative predictive value. 134 00:11:47,995 --> 00:11:58,915 In one really well conducted study, the positive predictive value of beta D glucan was 0%, but an extremely high beta D glucan can, can be indicative of pneumocystic pneumonia. 135 00:11:59,275 --> 00:12:03,224 I'd also be scouting the discussion about bronchoalveolar lavage. 136 00:12:03,445 --> 00:12:06,585 I think this kid's probably gonna need a BAL at some point. 137 00:12:07,665 --> 00:12:07,875 Tik Patel: Yeah. 138 00:12:07,875 --> 00:12:10,515 So the rest of the exposure history was unremarkable. 139 00:12:10,665 --> 00:12:13,214 No reports of frolicking through chicken coops. 140 00:12:14,265 --> 00:12:23,145 The lung exam was notable for decreased breath sounds in bases with a few end expiratory wheezes and no neck tenderness or oral lesions. 141 00:12:24,194 --> 00:12:34,995 He had urine legionella antigen, urine histoplasma antigen sent and serum mycoplasma titers and blood viral PCR for CMV, E BV, and adenovirus. 142 00:12:35,550 --> 00:12:44,219 He did have a 1,3-beta-D-glucan sent and his chest CT with contrast showed bilateral extensive airspace disease. 143 00:12:45,120 --> 00:12:45,390 Hmm. 144 00:12:46,829 --> 00:12:56,910 Josh Wolf: The story is a good one for pneumocystis pneumonia, with his lymphopenia, bilateral airspace disease and rapid regression of hypoxia to respiratory distress to respiratory failure. 145 00:12:57,449 --> 00:12:59,670 But you said that the patient was taking prophylaxis. 146 00:12:59,670 --> 00:13:00,420 Is that correct? 147 00:13:00,810 --> 00:13:03,819 I really, I would make sure that someone from our team goes and asks. 148 00:13:04,905 --> 00:13:05,355 Tik Patel: Yeah. 149 00:13:05,415 --> 00:13:09,075 And actually on the chest CT, the radiologist was concerned too. 150 00:13:09,435 --> 00:13:20,115 So the team went and asked the family about prophylaxis and the family admits to frequently missing doses and that he had actually run out of tablets last month and hadn't had a refill. 151 00:13:21,315 --> 00:13:26,325 So given this news, what would you recommend to the team in terms of management and any further workup? 152 00:13:26,865 --> 00:13:27,135 Josh Wolf: Wow. 153 00:13:27,135 --> 00:13:31,005 This really does push me towards a, a presumptive diagnosis of pneumocystis pneumonia. 154 00:13:31,005 --> 00:13:32,955 Although I wouldn't write off anything out. 155 00:13:33,915 --> 00:13:37,635 Um, so we are gonna start empiric therapy for pneumocystis while we figure this out. 156 00:13:37,855 --> 00:13:45,525 Um, and I, I think one really important take home point is that first, second and third line therapy for pneumocystis pneumonia is trimethoprim sulfamethoxazole. 157 00:13:45,885 --> 00:13:48,135 It's the best treatment far and away. 158 00:13:48,435 --> 00:14:00,605 And although it's usually well absorbed after oral administration, I typically start with IV dosing until I start seeing some improvement, especially in someone as sick as this I'd give, uh, five milligrams per kilogram, three to four times a. 159 00:14:01,560 --> 00:14:05,670 lower doses might be effective in milder disease, but it's not that well investigated. 160 00:14:06,480 --> 00:14:14,190 Um, and the role of steroids in a setting like this, if a severe pneumocystis infection in patients without HIV is really poorly understood. 161 00:14:14,760 --> 00:14:22,200 The big issue is that after you start treatment with antibiotics, the patients almost always get worse for about 48 hours before they turn the corner. 162 00:14:22,530 --> 00:14:25,350 And corticosteroids might prevent some of that deterioration. 163 00:14:25,990 --> 00:14:42,320 I, I almost always started into patients in the ICU with respiratory failure, but given the lack of evidence in a favor of it, if there's any contraindication or, uh, any changes in that suggest a steroid side effect, I have a low threshold for holding off or discontinuing it. 164 00:14:42,710 --> 00:14:46,160 And then the last thing is we're gonna work hard to confirm this diagnosis. 165 00:14:48,000 --> 00:14:48,180 Tik Patel: Yeah. 166 00:14:48,180 --> 00:14:52,860 And, and speaking about that, why is it so important to confirm the diagnosis of pneumocystis? 167 00:14:53,310 --> 00:14:54,160 Josh Wolf: Great question Tik. 168 00:14:54,660 --> 00:14:58,800 For one thing, you can stop alternative therapies and stop looking for alternative ideologies. 169 00:14:58,950 --> 00:15:04,050 But most importantly, high doses of trimethoprim sulfamethoxazole are really tough to take. 170 00:15:04,260 --> 00:15:05,440 It causes a lot of nausea. 171 00:15:05,460 --> 00:15:12,300 So in two weeks time, when he's throwing up or requiring a lot of anti emetics, it'll be good to be sure that we're treating the right thing. 172 00:15:12,960 --> 00:15:20,820 Uh, I think for his workup, I would be pushing for a bronchoalveolar lavage, or BAL given that other ideologies are still possible. 173 00:15:21,525 --> 00:15:26,955 Um, I'd be sending it for bacterial, fungal, viral, uh, and, uh, pneumocystis testing. 174 00:15:27,345 --> 00:15:38,925 And then the other test that seems to be potentially useful is metagenomic sequencing directly from blood, which is now commercially available in cases where BAL is impossible to get or potentially dangerous. 175 00:15:39,045 --> 00:15:41,635 This confirms the diagnosis of Pneumocystis. 176 00:15:42,030 --> 00:15:48,209 It's not first line because the sensitivity hasn't been that well evaluated yet, but it appears to be relatively specific. 177 00:15:48,719 --> 00:15:49,380 Tik Patel: Interesting. 178 00:15:49,469 --> 00:16:01,260 So, yeah, so he had a bronchoscopy with BAL, which was sent for the studies you mentioned, and the patient was started on IV trimethoprim-sulfa or Bactrim at treatment dosing with corticosteroids. 179 00:16:02,069 --> 00:16:11,099 And then three days later, his PJP PCR returned positive cytology done on the BAL was positive with cysts on the 180 00:16:11,955 --> 00:16:19,275 GMS stain or the silver stain and his one, three beta D glucan returned positive at greater than 500 picograms per ML. 181 00:16:19,695 --> 00:16:24,885 Josh Wolf: So this is a really classic case of, of, uh, pneumocystic pneumonia. 182 00:16:25,245 --> 00:16:28,785 Often we get only a handful of those tests positive. 183 00:16:28,785 --> 00:16:30,555 The cytology is often negative. 184 00:16:31,035 --> 00:16:40,025 Um, it can be difficult to get a BAL and the one, three B glucan being positive, such a high value is, is strongly suggestive. 185 00:16:41,025 --> 00:16:41,295 Tik Patel: Yeah. 186 00:16:41,295 --> 00:16:46,064 And so I think this was a case of PJP pneumonia in an immunocompromised teenager. 187 00:16:47,385 --> 00:16:56,444 So to introduce the bug, it was initially thought to be a protozoa and named Pneumocystis carinii, and now reclassified as a fungus with a new name. 188 00:16:57,314 --> 00:17:00,295 So there's whole specific strains with Pneumocystis carinii. 189 00:17:00,944 --> 00:17:05,700 Now the rat pathogen and Pneumocystis jirovecii is the human one. 190 00:17:06,030 --> 00:17:09,720 Sara Dong: Well, everyone's ID favorite, when we have to change the name of a bug, 191 00:17:10,080 --> 00:17:17,760 Josh Wolf: I've had to change from saying PCP to PJP or, and they promised us, this is something you don't know, when they changed the name. 192 00:17:17,760 --> 00:17:22,940 They promised us we could keep saying PCP, that it would stand for pneumocystis pneumonia. 193 00:17:25,829 --> 00:17:35,730 What happened instead was that young people started saying PJP and then old people who were saying PCP, the young people thought we just didn't know that it had changed and kept correcting us. 194 00:17:36,270 --> 00:17:41,730 Or they would just point pointedly say, well, PJP. 195 00:17:43,139 --> 00:17:45,090 It's terrible being old it sucks man. 196 00:17:45,090 --> 00:17:45,570 Okay. 197 00:17:45,570 --> 00:17:46,090 Sorry. 198 00:17:47,610 --> 00:17:48,210 Tik Patel: No worries. 199 00:17:49,485 --> 00:17:56,535 So this infection was first identified in malnourished, premature infants in Europe, in the 1950s by Jirovec and Vanek. 200 00:17:57,254 --> 00:18:10,004 And it was the first opportunistic infection associated with the aids epidemic at the start of 1981 and of the first 1000 cases of aids, 50% had a diagnosis of PJP. 201 00:18:11,655 --> 00:18:13,605 PJP has an interesting life cycle. 202 00:18:13,665 --> 00:18:17,024 There's two forms, the cyst and trophic form. 203 00:18:17,850 --> 00:18:21,720 Interestingly the GMs or the silver stain stains for the cyst form. 204 00:18:23,100 --> 00:18:29,550 And it seems to have a pretty, um, strong predominance or seropositivity in the, in the population. 205 00:18:30,150 --> 00:18:38,130 So if children, um, by age four, about 75% were seropositive for PJP. 206 00:18:39,750 --> 00:18:42,810 And a similar rate of colonization has been noted in autopsies. 207 00:18:43,169 --> 00:18:45,929 Of adults, uh, adult of adult lungs. 208 00:18:46,439 --> 00:18:49,350 So Josh, what are the risk factors for PJP related 209 00:18:49,350 --> 00:18:49,949 infection? 210 00:18:51,039 --> 00:18:54,090 Josh Wolf: Pneumocystic pneumonia is an opportunistic infection. 211 00:18:54,120 --> 00:18:56,969 It, it almost always causes only pneumonia. 212 00:18:56,975 --> 00:19:00,449 Although infections that other sites have been, uh, described. 213 00:19:01,560 --> 00:19:10,370 The important risk factors are, um, being HIV positive with, um, progressive lymphopenia and especially with a CD four count under 200. 214 00:19:11,280 --> 00:19:19,590 but that's a rare risk factor in pediatrics now in in high income countries, because kids with HIV are usually relatively well controlled. 215 00:19:20,370 --> 00:19:31,889 Other immunocompromised patients are also at risk and now make up the predominant source of patients with pneumocystic, pneumonia, uh, hematological malignancies, especially those 216 00:19:32,415 --> 00:19:37,335 acute lymphoblastic leukemia and solid or brain tumors within that population. 217 00:19:37,335 --> 00:19:40,365 Corticosteroid use is a really important risk factor. 218 00:19:40,845 --> 00:19:44,505 Transplant patients, either bone marrow transplant, or solid organ transplant. 219 00:19:44,925 --> 00:20:00,555 Some patients with primary immune deficiency, especially severe combined immunodeficiency, and then other patients who are immunosuppressed, such as those with chronic arthritidies or inflammatory bowel disease, especially with the use of more immunomodulatory medications. 220 00:20:02,085 --> 00:20:05,445 Tcell active agents, like alemtuzumab are the highest risk. 221 00:20:05,445 --> 00:20:19,365 And even though we typically think of T-cells as the most important for preventing Pneumocystis infection, agents that profoundly deplete B cells like rituximab or blinotumumab also increase the risk because of the interaction between B cells and T cells. 222 00:20:20,385 --> 00:20:34,065 We talk about a prednisone equivalent of two milligrams per kilogram per day, or greater than 20 milligrams per day total as sufficient to create a risk scenario, how it's unclear, whether corticosteroids alone are important risk factors in Pneumocystis in children. 223 00:20:35,055 --> 00:20:41,385 We do usually recommend prophylaxis, but there are some populations that have not received routine prophylaxis and seem to do okay. 224 00:20:41,715 --> 00:20:49,635 One example is boys with muscular dystrophy who receive corticosteroids for prolonged periods of time and don't seem to get pneumocystis. 225 00:20:49,875 --> 00:20:55,515 It might be a question of dose or of the complimentary immunosuppression from different agents that are given as well. 226 00:20:57,165 --> 00:20:57,675 Tik Patel: Great. 227 00:20:58,995 --> 00:20:59,655 So I know St. 228 00:20:59,655 --> 00:21:05,355 Jude has a long history in the study of PJ P and the investigation of treatments and prophylaxis. 229 00:21:05,745 --> 00:21:07,185 Can you tell us more about this? 230 00:21:08,340 --> 00:21:09,330 Josh Wolf: So certainly St. 231 00:21:09,330 --> 00:21:15,910 Jude, uh, has a long history of being involved with discovery around Pneumocystis. 232 00:21:16,590 --> 00:21:35,685 Um, in the 1960s, when we were just starting to use combination therapy for acute lymphoblastic leukemia, the first successes in, uh, cure of leukemia came with the cost of Pneumocystis in a very high proportion of cases. 233 00:21:36,375 --> 00:21:47,595 By the time we were in the 1970s and combination therapy for acute leukemia became routine, we were seeing very high rates of morbidity and mortality from pneumocystis infection and at St. 234 00:21:47,595 --> 00:21:56,985 Jude, Walter Hughes, who was the Chief of Infectious Diseases here started looking into this, both in the lab and in the clinic, he discovered that 235 00:21:57,824 --> 00:22:09,855 rats affected with pneumocystis, you could prevent pneumocystis infection and prevent death from pneumocystis infection with either Pentamidine or trimethoprim sulfamethoxazole. 236 00:22:10,304 --> 00:22:31,995 And he ran a clinical trial here, the only real clinical trial that has been, uh, done for trimethoprim-sulfamethaxazole against placebo for pneumocystis prevention in, uh, the mid seventies where he randomized patients with acute lymphoblastic leukemia to receive, uh, trimethoprim-sulfamethaxazole or placebo. 237 00:22:32,385 --> 00:22:35,595 And in the, after the first year of the study, it was clear. 238 00:22:35,595 --> 00:22:39,085 There was a benefit in terms of reduction of Pneumocystis. 239 00:22:39,399 --> 00:22:46,840 And a discussion took place about whether to unblind the study or to complete the two years that they had planned to run it for. 240 00:22:47,409 --> 00:22:56,409 He argued very strongly that this was our only chance to run a blinded placebo controlled study for pneumocystis prevention. 241 00:22:56,500 --> 00:23:16,230 And he was concerned that potential harms from the drug wouldn't become apparent until the second year of the study, he knew that the, uh, chemotherapy was gonna go on for a long time and he didn't wanna give this drug just for a short time and observe it without, uh, seeing whether there was long term harm. 242 00:23:17,205 --> 00:23:19,635 And a decision was made to complete the study. 243 00:23:19,725 --> 00:23:23,084 They didn't unblind until, uh, two years into the study. 244 00:23:23,264 --> 00:23:30,884 And at that point they showed that, um, Pneumocystis was almost 100% prevented with trimethoprim-sulfamethaxazole. 245 00:23:31,155 --> 00:23:50,630 He then went on to do, um, different randomized studies comparing, TMP-SMX against pentamidine for prophylaxis and two different regimens of TMP-SMX showing that, um, three times a week was as effective as daily TMP-SMX, but with reduced toxicity. 246 00:23:51,960 --> 00:23:53,220 Tik Patel: Well let me ask you about that. 247 00:23:53,220 --> 00:23:59,070 What are your thoughts on optimal trimethoprim-sulfa (Bactrim) prophylaxis for PJP nowadays? 248 00:23:59,070 --> 00:24:07,530 I see people doing daily, three times a week, either consecutive days versus Monday, Wednesday, Friday, two times a week. 249 00:24:07,535 --> 00:24:09,750 Like our patient was doing on the weekends. 250 00:24:10,230 --> 00:24:12,470 Is there a correct regimen or do they all work? 251 00:24:12,970 --> 00:24:16,440 And then how long should prophylaxis be continued for different populations? 252 00:24:17,250 --> 00:24:26,370 Josh Wolf: The randomized controlled evidence really best supports three consecutive days per week, uh, over daily as providing a balance between extremely high efficacy and low toxicity. 253 00:24:26,760 --> 00:24:34,470 But a lot of other regimens such as once or twice weekly or three non consecutive days are all supported by observational studies and probably work. 254 00:24:35,020 --> 00:24:35,380 At St. 255 00:24:35,380 --> 00:24:43,170 Jude, we give three consecutive days a week and our feeling is that it allows for some non-adherence, it's well tolerated and very effective. 256 00:24:44,070 --> 00:24:45,540 How long do you need to continue? 257 00:24:45,945 --> 00:24:49,245 We typically continue until after completion of therapy and steroids. 258 00:24:49,425 --> 00:24:57,945 And we continue about six weeks after this and we'll often give longer therapy if they're receiving therapies that deplete immune cells. 259 00:24:58,035 --> 00:25:00,675 For transplant patients, it's a little more complicated. 260 00:25:00,915 --> 00:25:20,215 They'll continue as long as they're receiving immunosuppressive medication and there's some interest in this population using T-cell subset analysis to stop prophylaxis, but it's really not well established outside the HIV world where a stable CD4 count above 200 is used as a cutoff to discontinue prophylaxis in adults and older children, at least. 261 00:25:20,905 --> 00:25:21,295 Tik Patel: Yeah. 262 00:25:21,355 --> 00:25:22,105 Thank you for that. 263 00:25:22,110 --> 00:25:28,045 So I think that's very important to keep in mind, especially in this case, because there was suboptimal prophylaxis. 264 00:25:29,035 --> 00:25:35,180 Now, what are the options if there is TMP-SMX intolerance, adverse events or a contraindication? 265 00:25:36,360 --> 00:25:38,580 Josh Wolf: I think there are a few things to think about in this setting. 266 00:25:38,580 --> 00:25:45,000 Firstly, all of the alternative prophylaxis regimens are likely to be inferior protection against pneumocystis. 267 00:25:45,780 --> 00:25:51,090 Secondly, contraindications for TMP-SMX are frequently over called. 268 00:25:51,480 --> 00:25:58,210 Marrow suppression from three days a week therapy is overdiagnosed and the drugs should be re trialed if that's ever a possibility. 269 00:25:58,595 --> 00:26:02,524 And then thirdly, a break from prophylaxis for up to 14 days is safe. 270 00:26:02,705 --> 00:26:08,345 So it's okay to stop the drug and not start an alternative for a couple of weeks while you sort out whether to re challenge. 271 00:26:09,245 --> 00:26:19,145 But if we need an alternative aerosolized or IV pentamidine, oral dapsone or oral atovaquone are all similarly available and effective. 272 00:26:20,700 --> 00:26:22,950 Tik Patel: and now million dollar question. 273 00:26:23,070 --> 00:26:26,010 Do you think of the alternatives in terms of priority? 274 00:26:26,040 --> 00:26:29,430 Like would you go to one versus the other or are they all the same? 275 00:26:30,450 --> 00:26:39,060 Josh Wolf: Yeah, my personal approach is to use Pentamidine and I, I used IV or aerosolized without a clear preference for one over the other, unless one's contraindicated. 276 00:26:39,510 --> 00:26:47,490 As the next line of prophylaxis, we recently looked back at the St Jude experience with IV and inhaled pentamidine and found that it was well tolerated. 277 00:26:47,735 --> 00:26:52,925 And the breakthrough infections, even using a very broad definition to catch all possible cases was really rare. 278 00:26:53,885 --> 00:26:58,535 Dapsone has cross reactivity with trimethoprim-sulfa so we don't use it in allergy. 279 00:26:58,985 --> 00:27:01,355 And atovaquone solution tastes terrible. 280 00:27:01,360 --> 00:27:07,565 So adherence is pretty tough in kiddos, but any of these are acceptable and I don't think there's a clear winner. 281 00:27:08,435 --> 00:27:08,975 Tik Patel: Awesome. 282 00:27:10,055 --> 00:27:12,965 Well, how about we get into something a little bit more controversial. 283 00:27:13,365 --> 00:27:23,985 So let's say our patient getting therapy did not improve significantly in the ICU, continuing to acquire mechanical ventilation after starting treatment for a few days. 284 00:27:24,405 --> 00:27:27,795 Is there such thing as PJP resistance to TMP-SMX? 285 00:27:28,455 --> 00:27:33,525 And if so, are there other treatments you would consider a second line or salvage therapy? 286 00:27:34,305 --> 00:27:40,645 Josh Wolf: There's definitely no clear evidence of clinically relevant resistance to TMP-SMX. 287 00:27:41,205 --> 00:27:52,500 There are certainly mutations that, uh, decreased the, um, in vitro effect of TMP-SMX on Pneumocystis but it's not translated into clinical failure. 288 00:27:53,280 --> 00:27:56,699 And so there's no role for resistance testing. 289 00:27:57,330 --> 00:28:03,639 If there's no response to therapy after four to seven days, I might consider switching or reconsidering my diagnosis. 290 00:28:03,639 --> 00:28:06,670 Have I got the wrong diagnosis or is there a co-infection. 291 00:28:07,480 --> 00:28:15,190 Second line therapy is with clindamycin plus primaquine or with IV pentamidine, but it's really rarely required in clinical practice. 292 00:28:15,190 --> 00:28:17,649 They usually start turning the corner within that period. 293 00:28:18,450 --> 00:28:19,010 Tik Patel: Great. 294 00:28:19,010 --> 00:28:19,730 Thank you. 295 00:28:20,710 --> 00:28:25,330 And lastly, I've seen some literature describing the use of echinocandins with PJP. 296 00:28:25,740 --> 00:28:27,210 Can you talk a little bit about that? 297 00:28:28,080 --> 00:28:28,710 Josh Wolf: Yes. 298 00:28:28,920 --> 00:28:39,060 The cyst form of Pneumocystis does have 1,3-beta-D-glucan in the cell wall, and there's in vitro and animal data suggesting that it might improve outcomes. 299 00:28:39,570 --> 00:28:49,754 There's certainly case report data and some retrospective study that suggests that caspofungin plus TMP-SMX might be superior to TMP-SMX alone. 300 00:28:50,205 --> 00:28:53,715 But really I think that the evidence is very weak right now. 301 00:28:53,955 --> 00:28:55,455 I don't use it routinely. 302 00:28:55,575 --> 00:29:05,475 It's something I might consider, uh, adding in a case of poor clinical response and certainly a echinocandin is a well tolerated and a reasonable thing to try. 303 00:29:05,835 --> 00:29:07,575 Uh, it's not part of my usual practice yet. 304 00:29:09,675 --> 00:29:09,975 . Yeah. 305 00:29:10,665 --> 00:29:26,145 Sara Dong: Well, I am so grateful that you guys both came on to talk about this, cuz I think that I maybe often we don't realize how little sometimes we know about translating some of the data from PJP into other immunocompromised host. 306 00:29:26,535 --> 00:29:37,395 Um, and I think a lot of times we actually don't see this that much anymore, but at the end I always open it up to check to see if there's anything you guys think we missed or any sort of final, final parting words. 307 00:29:38,864 --> 00:29:43,004 Tik Patel: Often we focus on neutropenia for our patients with cancer and risk of infection. 308 00:29:43,004 --> 00:29:50,415 But as demonstrated in this case, I urge folks to pay attention to the rest of the differential as well, including absolute lymphocyte count. 309 00:29:51,435 --> 00:30:04,615 Josh Wolf: I agree Tik, getting to a, a nuanced understanding of the nature and the degree of immunocompromise is essential for an individual patient or a group of patients thinking about which components of the immune system are compromised, how profoundly and for how long 310 00:30:04,745 --> 00:30:08,965 should influence your management, it makes you a better doctor and it can help you pass boards. 311 00:30:10,065 --> 00:30:11,475 Sara Dong: Well what an ending. 312 00:30:11,504 --> 00:30:15,945 That's a perfect description of what I hope a lot of the Febrile episodes can do. 313 00:30:16,514 --> 00:30:20,504 Um, so thanks to Josh and Tik for joining Febrile today. 314 00:30:20,565 --> 00:30:28,514 Don't forget to check out the website, febrile podcast.com, where you can find the Consult Notes, which are written complements of the show with links to references, 315 00:30:28,885 --> 00:30:32,335 our library of ID infographics and a link to our merch store. 316 00:30:32,455 --> 00:30:37,975 Please reach out if you have any suggestions for future shows or want to be more involved with febrile. 317 00:30:38,065 --> 00:30:38,965 Thanks for listening. 318 00:30:38,965 --> 00:30:40,885 Stay safe, and I'll see you next time.