12/7 HUP Report: Disseminated Cryptococcus

Thanks to Dr. Barton for being our faculty expert today to discuss a case of disseminated Cryptococcus! The patient we discussed today did not have the usual risk factors for this infection, which we typically think about in patients who have compromised cellular immunity. Particular patient populations at risk include patients with HIV, hematopoietic stem cell transplant recipients, and solid organ transplant recipients.

Cryptococcus is a budding yeast with a capsule, seen here on silver stain:

CR1                                   http://englishdictionary.education/en/cryptococcus

The most common sites of Cryptococcus infection are the lungs and the CNS. It can also cause skin infection, particularly in HIV patients, which can resemble molluscum in appearance. If Cryptococcus is cultured from any other organ, it should be treated as disseminated infection.

CR2

https://www.researchgate.net/figure/232279838_fig2_Figure-1-The-dissemination-model-of-Cryptococcus-neoformans-from-the-environment-to-the

Although disseminated Cryptococcus and cryptococcal meningitis should be treated with the same medications, it is still important to perform an LP in someone with cryptococcemia to check opening pressure — it is frequently elevated in patients with CNS involvement of disseminated Cryptococcus, which can have serious consequences and may require treatment with CSF removal.

Below are guidelines for treatment of disseminated Cryptococcus in non-HIV non-transplant hosts, from the Infectious Disease Society of America. Basically, there are three stages of treatment: induction, consolidation, and maintenance. The induction phase should involve a combination of amphotericin and flucytosine, followed by consolidation with high dose fluconazole and maintenance with lower dose fluconazole.

CR3

See below for a reference of a case report similar to our own patient!

References:

Okamoto K, Proia LA, Demarais PL. Disseminated Cryptococcal Disease in a Patient with Chronic Lymphocytic Leukemia on Ibrutinib. Case Rep Infect Dis. 2016;2016:4642831. Epub 2016 Sep 14.

 

 

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12/4 Presby report: relapsing fevers, EBV serologies

A big thanks to Robin for presenting the case of an older man who developed high fevers that disappeared and then relapsed, along with cytopenias and LFT abnormalities, and was ultimately diagnosed with Anaplasma. There was a lot of rich discussion during this case!

What defines a fever?

  • Normal body temperature fluctuates throughout the day, with temps lower in the morning (max 98.9F) and higher in the evening (max 99.9F)
    • so whether you call something a fever or not may depend on the time of day; the cutoff of 100.4F that we’ve come to use is in some ways quite arbitrary

There’s no strict definition of ‘relapsing’ fever; there just has to be some fever-free interval (generally at least 24-48h) before the fevers start again.

  • Keep in mind that several etiologic organisms cause fevers in a relapsing pattern, and that there is also an entity called ‘relapsing fever’ which is caused specifically by several Borrelia species

Causes of relapsing fever

  1. Tick-borne relapsing fever (TBRF): caused by Borellia spp (parkeri, turicatae, hermsii) and transmitted by SOFT ticks like Ornithodoros (different from hard ticks like Ixodes which transmit Lyme, Babesia, etc). Main risk factor: rodent exposure
  2. Louse-borne relapsing fever (LBRF): caused by Borellia recurrentis and transmitted by human body louse. Mostly limited to Africa.
  3. Borellia miyamotoi: a newly described pathogen, transmitted by hard ticks which can be contracted in the Northeast US
  4. Leptospirosis
  5. Rare: anaplasma, ehrlichia
  6. Malignant fevers, particularly Pel-Ebstein fevers from Hodgkin’s lymphoma

 

Lastly, we talked about EBV serology interpretation. Remember that most people get EBV in childhood.

EBV testing has three components: viral capsid antigen (VCA) IgG, VCA IgM and Epstein-Barr Nuclear Antigen (EBNA)

  • The EBNA will stay elevated indefinitely after infection, so if it’s elevated, that indicates past infection
  • If the VCA IgM is elevated and EBNA is not, that likely indicates recent infection
  • The VCA IgG is really ‘corroborative’ and remains elevated after past infection

 

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Interpretation of EBV serologies

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Source: Mayo Medical Laboratories. Note: *Results indicate infection with EBV at some time (VCA IgG positive). However, the time of the infection cannot be predicted (ie, recent or past) since antibodies to EBNA usually develop after primary infection (recent) or, alternatively, approximately 5% to 10% of patients with EBV never develop antibodies to EBNA (past).

 

References

  1. Barbour A. Harrison’s Principles of Internal Medicine. “Relapsing Fevers”.

11/15 HUP Report: Infectious Endocarditis

Thank you to Dr. Amorosa for teaching us about advanced management of infectious endocarditis! Today we discussed the case of a young male IV drug user who presented with fever, new cardiac murmur, and evidence of embolic phenomena on his skin exam who was found to have MRSA endocarditis.

When dealing with a case of suspected endocarditis, make sure you get cultures!! This is really important – in the majority of cases cultures will identify an organism and allow for targeted treatment. Ideally, at least two sets of cultures separated in space and time (at least thirty minutes) should be collected. While waiting for this data, if empiric treatment is necessary clinically, consider covering strep, staph (MRSA and MSSA), and enterococcus species.

In cases of MSSA endocarditis, a bacteriocidal agent such as nafcillin or oxacillin is usually recommended; addition of aminoglycoside has not shown clinical benefit and confers the downside of lots of potentially permanent and serious side effects, so their synergistic use has fallen out of favor. In cases of MRSA endocarditis, vancomycin is usually a good first line agent. Coagulase negative staph should be treated like MRSA.

We also discussed surgical interventions in patients with endocarditis. There has been a recent trend toward increased discussion of early surgery (performed before the completion of the initial antibiotic course), especially in cases where the infection has been demonstrated to be causing valvular disease and subsequent heart failure (as in our patient), perivalvular abscess or extension, and other difficult-to-treat situations. Here is some data to support early surgery in cases similar to ours:

  1. This study published in JAMA (full reference below) was a prospective, multicenter study of n= 4166 patients with infective endocarditis. The researchers looked to see which factors were associated with mortality among the patients. Of patients with heart failure symptoms (classified into NYHA classes), those who underwent early surgery had improved in-hospital mortality rates. (Of course, there are confounding factors to consider here).

IE1.png

2. This study from the Journal of Thoracic Cardiovascular Surgery (full reference below) retrospectively reviewed n=212 patients with left-sided native valve infective endocarditis. Early surgery was defined as occurring within 2 weeks of initial diagnosis. They found that in patients who received early surgery, there was statistically significant reduction in IE-related death and major adverse cardiac event (again, there are caveats here too!)

IE2.png

Infectious endocarditis can be difficult to treat. Always get infectious disease colleagues involved! And consider early surgical intervention if clinically indicated. Sadly, this disease is one of the many health hazards that accompanies the opioid epidemic.
References:

Kiefer et al. Association between valvular surgery and mortality among patients with infective endocarditis complicated by heart failure. JAMA 2011; 306(20):2239-2247.

Funakoshi et al. Impact of early surgery in the active phase on long-term outcomes in left-sided native valve endocarditis. J Thorac Cardiovasc Surg 2011;142:836-42.

 

 

11/7 HUP Report – Acute Liver Failure due to HSV

Thanks to Dr. Khungar for joining our discussion about a very interesting case. Today we discussed a patient with a history of poorly-managed SLE who was hospitalized with concern for pleuritis/pericarditis and rapidly developed acute liver failure. In a matter of a couple days this patient’s liver function tests went from normal to peak values of AST >14000, ALT >6000, Alk Phos 144 and T. Bili 9.6.

We reviewed the clinical definition of acute liver failure:

ALF

Our patient met criteria for acute liver failure. Within the broad differential for this condition, there are not all that many pathologies that will cause transaminase elevation to the degree seen in our patient. Some things to think about include:

  • drug induced liver injury
  • acetaminophen overdose
  • ischemic liver injury
  • viral hepatitis (rarely)
  • HSV

Care for acute liver failure involves supportive measures and evaluating for liver transplantation. We also discussed some data suggesting benefit to administration of N-Acetylcysteine (NAC) even in patients who did not overdose on acetaminophen.

In a prospective, double-blind trial published in Gastroenterology, acute liver failure patients without clinical or historical evidence of acetaminophen overdose were stratified by site and coma grade and assigned randomly to groups that were given NAC or placebo (dextrose) infusion for 72 hours. The primary outcome was overall survival at 3 weeks. Secondary outcomes included transplant-free survival and rate of transplantation.

Transplant free survival was significantly better in patients receiving NAC, with the most notable benefit in patients with coma grades I–II.

alf2

Our patient received an orthotopic liver transplant, and her explanted native liver stained positive for HSV. This is a rare cause of acute liver failure but should remain on your differential, particularly in patients at risk (including pregnant women or patients with compromised cellular immunity).

 

References:

Lee, WM et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology. 2009 Sep;137(3):856-64, 864.e1. doi: 10.1053/j.gastro.2009.06.006. Epub 2009 Jun 12.

 

 

11/2 Presby report: summer fever, HACEK endocarditis

Thanks for Dr. Judy O’ Donnell for lending her expertise with the case of an older dentist who came in with several weeks of fevers during the summer, found to have HACEK (H. parainfluenza) endocarditis!

The problem representation of a summer fever can help you create your differential

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Remember the Duke criteria for endocarditis (major criteria boxed in red)

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NEJM 2013

The main indications for surgical treatment of endocarditis are:

  1. Heart failure
  2. Uncontrolled infection (particularly with organisms that won’t clear with just antimicrobial therapy, especially Candida spp)
  3. Prevention of embolization

Ideally, blood cultures should clear before the patient goes to the OR but that is not always possible.

This patient ended up growing Hemophilus parainfluenzae, which is part of the HACEK group of organisms. HACEK bugs used to be poorly culture-able, but with advances in technology, they generally grow out of standard blood culture bottles within 4-5 days.

Certain species are more prone to embolization than others

  • Staph aureus
  • Pneumococcus
  • Group A and Group B strep
  • Candida

Final pearls

  • if you have a normal LP (normal cell counts, etc) but still suspect an infectious cause of non-specific fever, a Lyme PCR and maybe West Nile testing may still be useful as they can occasionally present with a normal LP
  • West Nile Virus can cause a nonspecific febrile illness, although usually <2 weeks in duration
  • mitral valve vegetations are more prone to embolization than other valves because flow across that valve is more turbulent than across other valves

References

  1. Hoen et al. Infective Endocarditis. NEJM 2013.
  2. Hu et al. Case 24-2015. NEJM 2015.
  3. Mourad et al. A comprehensive evidence-based approach to fever of unknown origin. JAMA 2003.

10/30 Presby report: prosthetic joint infection

Local badass SAR Aaron Pulsipher presented a fascinating and perplexing case of a middle aged woman with pancreatic cancer who presented with bilateral (prosthetic) knee pain and is now felt to have culture-negative prosthetic joint infection (PJI).

What are signs/symptoms of prosthetic joint septic arthritis?

  • acute infection (especially immediately post-op): pain, swelling, erythema of joint
  • chronic infection: pain alone, loosening of joint, sometime sinus tract formation

How’s it diagnosed?

  • Consider sending a CRP (95% sens, 60% spec at cutoff of 5 for dx of PJI)
  • X-rays are likely not helpful, and CT/MRI may be hampered by artifact from the prosthesis
    • Bone or PET scans could be considered, but probably requires discussion with ortho
  • Synovial fluid analysis

First, a review of synovial fluid analysis:

Screen Shot 2017-10-30 at 1.53.33 PM.png

Septic arthritis often has synovial fluid WBC counts >100K. Remember that these WBC ranges often overlap; the higher the WBC count, the more likely it is to be infectious, but a high WBC count (say 70K) could still be due to non-infectious (especially crystalline). UpToDate: “Synovial Fluid Analysis”

IMPORTANT: WBC cutoffs are much lower for diagnosis of prosthetic-joint septic arthritis than for native joint septic arthritis

  • >1700 WBC or >65% PMNs: consistent with prosthetic knee infection
  • >4200 WBC or >80% PMNs: consistent with prosthetic hip infection
    • Another study references a much lower cutoff of >1400 WBCs for hip PJI, so have a lower threshold to suspect it

Periprosthetic tissue can also be submitted for culture from the OR, but multiple samples have to be cultured due to the poor sensitivity of one specimen.

Screen Shot 2017-10-30 at 1.45.42 PM.png

NEJM 2009

Bacteria love to form biofilms on the surface of the prosthesis, so culture of the prosthesis is extremely important to establishing the diagnosis

Here’s a brief algorithm that goes over treatment:

Screen Shot 2017-10-30 at 2.47.22 PM.png

NEJM 2009

 

 

References

  1. Infection Associated With Prosthetic Joints. NEJM 2009.
  2. Dinneen et al. Synovial fluid white cell and differential count in the diagnosis or exclusion of prosthetic joint infection. Bone and Joint 2013.
  3. Synovial Fluid Analysis. Uptodate.

 

10/26 Presby report: meningitis, gram negative coccobacilli

Thanks to Jeff Cherng for presenting a very interesting case today: a 36 y/o MSM presenting with fever, headache and diarrhea. We talked about ALL kinds of stuff, so I’ll give you a little sampling here:

What physical exam maneuvers have been studied for the diagnosis of meningitis?

Screen Shot 2017-10-26 at 9.49.27 AM

Both Kernig’s and Brudzinski’s signs are overall not that helpful: a recent analysis suggested that both signs are only ~5% sensitive, ~95% specific, with a PPV ~25%; really not that helpful, since with meningitis (a ‘can’t miss’ diagnosis), you want to maximize sensitivity.

Screen Shot 2017-10-26 at 4.50.16 PM.png

There’s also the Hoyne (aka Amoss) sign, which is a form of tripoding associated with intense meningeal irritation; pts may assume this posture to alleviate the meningismus

We talked about the utility of a pre-LP CT scan. See the IDSA algorithm below, but the punchline is that most patients do NOT need a CT. You should really only be scanning those patients in whom you’re concerned about a mass lesion (see the red box below).

Screen Shot 2017-10-26 at 5.10.55 PM

IDSA guidelines: “Management of Bacterial Meningitis”

Remember that different immunosuppressive drugs put you at risk for different infections. See this old post for details.

Adjunctive dexamethasone

  • Mechanism: reducing intracranial inflammation so as to reduce mortality and long term sequelae of meningitis (intellectual disability, seizures, deafness, etc)
  • studied in both developed and developing countries, and has been found to be specifically beneficial in S. pneumo meningitis mostly in developed countries (although a Vietnamese study did show a mortality benefit in the subgroup of its patients that wound up growing S. pneumo)
  • Not totally clear why this benefit doesn’t exist in the developing world, but may have to do with increased incidence of TB and crypto meningitis (relative to the Western world), malnutrition and HIV/AIDS
  • Dosing: 10mg IV dexamethasone q6h x 4 days. Stop if cultures negative or grow something other than S. pneumo.

Lastly, a list of gram negative cocci and coccobacilli (since this pt ended up growing H. flu from his blood).

  • Gram negative cocci
    • Neisseria gonorrhea
    • Neisseria meningitidis
    • Moraxella catarrhalis
    • Veillonella (very rare)
  • Gram negative coccobacilli
    • Hemophilus species (influenzae, ducreyi)
    • Acinetobacter
    • Kingella (HACEK endocarditis)
    • Francisella (aka tularemia)

References

  1. De Gans J et al. Dexamethasone in adults with bacterial meningitis. N Engl J Med. 2002 Nov 14;347(20):1549-56.
  2. Attia et al. The Rational Clinical Exam: Does this Adult Patient Have Acute Meningitis? JAMA 1999
  3. Thomas KE et al. The diagnostic accuracy of Kernig’s sign, Brudzinski’s sign, and nuchal rigidity in adults with suspected meningitis. Clin Infect Dis 2002 Jul 135:46-52.