Tag Archives: #FOAMed

COVID-19 Ultimate Resource List

There’s so much information about the novel coronavirus COVID-19 on the internet that it is hard to keep up with the onslaught of information. We wanted to compile the ultimate list of reputable resources for clinical providers to access when they need to, at a moment’s time.

Since information on COVID-19 is rapidly changing, these resources are not specific papers or blog posts, but rather websites that are maintaining up to date information on epidemiology, pathophysiology, and management. Resources span all types, including website behemoths like the WHO and CDC, as well as twitter accounts for people who get their news from social media.

Since this is an ultimate list but we don’t pretend to have ultimate knowledge of all resources, please send us resources that we may have missed and we will add them on here! We also acknowledge that this list is U.S. centric because we are from the States, but we would love input on resources for other countries so we can make this a more international list.

For the most up to date information:

Epidemiology:

Academic:

Clinical/Practical Management:

  • University of Washington – the holy grail of practical documents developed by people who are currently battling a COVID-19 outbreak. All documents can be utilized by others and adapted for their own institutional protocols.
  • University of Kentucky – have assessment, triage, and testing algorithms for use
  • University of Nebraska Medical Center – fantastic protocols on donning on/off PPE, videos, as well as other in-hospital quarantine protocols
  • IDStewardship – a very thorough, but easily read overview of potential treatment options for COVID-19 and how/when to use them
  • University of Liverpool – charts on drug drug interactions with experimental therapies for COVID-19
  • CIDRAP – focuses on the health policy aspect of COVID-19 news
  • Society of Critical Care Medicine – online training modules for disaster medicine, resource availability in U.S., and other fantastic resources for front-line clinical providers

Immunocompromised hosts:

Clinical Trials:

  • ClinicalTrials.gov – a currently-recruiting randomized controlled trial of remdesivir for COVID-19 treatment
  • CURE ID –  an FDA and NIH supported website where you can report and see new uses of existing drugs for difficult-to-treat infectious diseases. Download their mobile app too!

Blogs:

Podcasts:

  • TWiV – a podcast by virologists discussing virology; with recent episodes on COVID-19
  • IDSA Podcast – has weekly podcast series “Coronavirus: What’s happening now?”
  • JAMA Clinical Reviews – recent episodes on COVID-19 from various different viewpoints
  • NEJM Interviews – hosts short and to the point interviews with world experts

Twitter accounts:

Graphics:

Graphics Reuters – for the graphic enthusiasts out there
New York Times Coronavirus Maps – for the graphic enthusiasts out there

That’s it for now! Let us know if we missed any great resources!

Thank you for all the work that all of you do. Stay safe!

This list was compiled by Milana Bogorodskaya, Fatima Al-Dhaheri, and Ahmed Abdul Azim.

Histoplasma Capsulatum

Learning about fungi is hard enough even for infectious disease fellows (Narrator: especially for infectious disease fellows). By the time you learn how to differentiate the yeasts from the molds, the fungi kingdom decides to throw you a curve ball: Enter the shape shifters into the game of fungi learning – the dimorphic fungi.

The Dimorphic fungi shape shift depending on the weather (literally). They exist as molds in the great outdoors (environmental temperatures) and yeasts in the great indoors (inside our bodies at body temperatures). Clinically, this also means you will see the yeast forms in a histopathology review of a tissue sample, and our friends in the microbiology lab can re-create the environmental factors to grow them out as mold forms in culture. So essentially, they also shape shift between the microbiology lab and the pathology department. (They are sneaky Fung(uy)i…)

This is the first post out of 6 and will focus on our first shapeshifter, Histoplasma capsulatum.

CLICK HERE for a 2-page PDF handout of this information.

Morphology:(3)

  • At 25°C-30°C (mold form):Young cultures – septate hyphae with smooth or spiny microconidia
  • Older cultures (several weeks old) – large, thick walled round macroconidia with knobby projections (Image)
  • At 37°C (yeast form): small, round budding cells 

Geography, Reservoir and Mode of Transmission:

  • Histoplasma has a world-wide distribution(4), but is mostly endemic in the Americas (Central/Eastern United States & Central and South America)
  • Reservoir includes: soil, areas of construction, animal droppings (i.e. bats – a board favorite!), and caves (another board favorite)
  • Mode of transmission: aerogenic

Clinical presentation:

  • Known as the ‘syphilis’ of the fungal world because it’s a great imitator, particularly of TB(4).
  • Disease presentation/severity depends on size of inoculum & immune status
    • Immunocompetent hosts: usually asymptomatic/self- limiting
    • Immunocompromised hosts: often progressive/severe/disseminated
  • Can present as:
    • Acute pulmonary disease: Either as diffuse or localized infiltrates +/- mediastinal lymphadenopathy
    • Chronic pulmonary disease: Cavitary lesions/nodules
    • Mediastinal disease: Mediastinal granulomas and fibrosis

Diagnosis:

1. Culture:

  • *Please alert the microbiology lab if you suspect histoplasmosis and are sending them cultures! (culture needs to be specially handled in the lab due to risk occupational transmission/infection (just like all dimorphic fungi covered in this review).
  • Sensitivity of both tissue and blood cultures depend on the presentation (pulmonary vs. disseminated), immune status and burden of disease(5)
  • Disseminated disease → ~74% will have positive cultures(6)
  • Pulmonary disease → ~42% will have positive cultures(6)
  • HIV/AIDS patients:
    → ~ 90% of respiratory cultures will be positive(7)
    →~50% of blood cultures will be positive(7)

2. Histopathology:

  • Appear as yeast form, predominantly phagocytosed within macrophages and histiocytes
  • Presence in tissue supports diagnosis, although does not necessarily indicate active infection (could be detected in non-active granulomas for years)
  • Characteristic pathology feature is the presence of granulomas (caseating or non-caseating)(6)

3. Antigen detection:

  • Preferred method of testing: rapid testing + non-invasive + highly sensitive.
  • Sensitivity: urinary antigen > serum antigen (across all spectrum of clinical presentations of histoplasmosis)(9)
  • Histoplasma serum antigen (MiraVista© EIA) have highest sensitivity in disseminated disease (91.8%) >chronic pulmonary disease (87.5%) >acute pulmonary disease (83%) >subacute histoplasmosis (30%)(8)
  • In HIV/AIDS patients with disseminated disease, Histoplasma antigen can be detected in 95% of cases
  • Mediastinal involvement in histoplasmosis (mediastinal granuloma, mediastinitis) doesn’t usually result in positive antigen testing
  • Histoplasma antigen can cross react with all the dimorphic fungi covered in this review series (less commonly for coccidioides spp.)

4. Serology:

  • Antibodies take 4-8 weeks to become detectable therefore not useful for acute diagnosis but can be helpful for subacute and chronic forms of the disease
  • Titers usually decrease with disease resolution, but slowly so titers cannot be used to monitor for treatment response
  • Immunocompromised patients, particularly those with humoral defects, might not mount an antibody response so serology testing isn’t as useful.

5. Molecular methods:

  • No currently FDA approved molecular assay for H. capsulatum for clinical use.
  • PCR assays available in reference labs but are not yet standardized

Management(12):

Clinical presentationMild/ModerateModerate/SevereChronic
Pulmonary<4weeks: none
>4weeks: itraconazole for 6-12 months
Lipid amphotericin B for 1-2 weeks followed by itraconazole for 12 weeksItraconazole for 12 months
DisseminatedItraconazole for 12 monthsLipid amphotericin B for 1-2 weeks followed by itraconazole for 12 monthsN/A

References:
1. Climate change: the role of the infectious disease community. Lancet Infect Dis. 2017; 17:1219.
2. Greer A, Ng V, and Fisman D. Climate change and infectious diseases in North America: the road ahead. CMAJ. 2008; 178:715–722.
3. Walsh, TJ, Hayden, RT, and Larone, DH. Larone’s medically important fungi, 6th edition, ASM press, 2018.
4. Queiroz-Telles F, Fahal AH, Falci DR, et al. Neglected endemic mycoses. Lancet Infect Dis. 2017;17:e367–e377.
5. Azar MM and Hage CA. Laboratory Diagnostics for Histoplasmosis. J Clin Microbiol. 2017; 55:1612–1620.
6. Hage CA, Azar MM, Bahr N, Loyd J, and Wheat LJ. Histoplasmosis: up-to-date evidence-based approach to diagnosis and management. Semin Respir Crit Care Med. 2015; 36:729–745. 
7. Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev. 2007;20:115–132.
8. Hage CA, Ribes JA, Wengenack NL, et al. A multicenter evaluation of tests for diagnosis of histoplasmosis. Clin Infect Dis. 2011;53:448–454. 
9. Wheat LJ and Kauffman CA. Histoplasmosis. Infect Dis Clin North Am. 2003;17:1–19.
10. Swartzentruber S, Rhodes L, Kurkjian K, et al. Diagnosis of acute pulmonary histoplasmosis by antigen detection. Clin Infect Dis. 2009; 49:1878–1882. 
11. Saccente M and Woods GL. Clinical and laboratory update on blastomycosis. Clin Microbiol Rev. 2010;23:367–381.
12. Wheat LJ, Freifeld AG, Kleiman MB, et al; Infectious Diseases Society of America. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis. 2007;45:807–825.

The Shape Shifters: Dimorphic fungi

Learning about fungi is hard enough even for infectious disease fellows (Narrator: especially for infectious disease fellows). By the time you learn how to differentiate the yeasts from the molds, the fungi kingdom decides to throw you a curve ball: Enter the shape shifters into the game of fungi learning – the dimorphic fungi.

The Dimorphic fungi shape shift depending on the weather (literally). They exist as molds in the great outdoors (environmental temperatures) and yeasts in the great indoors (inside our bodies at body temperatures). Clinically, this also means you will see the yeast forms in a histopathology review of a tissue sample, and our friends in the microbiology lab can re-create the environmental factors to grow them out as mold forms in culture. So essentially, they also shape shift between the microbiology lab and the pathology department. (They are sneaky Fung(uy)i…)

Some of the clinically relevant dimorphic fungi have a predilection for geographical location (endemic mycoses), and therefore are very popular in board exams to the dismay (or joy, after this review series?) of medical trainees.

#ClimateChangeIsReal isn’t just pertinent in the political arena, but also for these endemic fungi. The grave consequences of climate change might change and expand the geographical distribution(1,2) of these fungi and therefore result in more catch-up learning on our end. This is almost akin to learning the constant re-classification and re-naming of the fungi kingdom (thanks, no thanks taxonomists…)

In this review series, I will go over the endemic fungi in a ‘high yield’ approach that will hopefully be pertinent for both shelf exams/boards and clinical practice.

I’ve also purposefully made it a two-pager/per fungi review (or 1 pager if you print it double-sided, #SaveTheTrees). We will be providing PDF links with every Fungi review. This will be an easy reference for a pocketbook, handouts to print to teach your medical students or if you want to flex your knowledge of endemic fungi during rounds (All win-win-win situations!)

The profile of each shape shifter will be released every Friday in the spirit of #FungalFriday. The dimorphic fungi that will be covered during the #ShapeShifterSeries include:

  • Histoplasmosis
  • Blastomycosis
  • Coccidioidomycosis
  • Talaromycosis
  • Paracoccidiomycosis
  • Sporotrichosis

Our First Shape shifter in the series to be released this coming #FungalFriday will be Histoplasmosis, aka the Ohio valley disease/Cave disease. What does Ohio or caves for the matter have to do with this Fungus? Find out more this coming Friday!

Fatima Al Dhaheri, MBBS
The Fung(uy)i squad

References:
1. The Lancet Infectious Diseases. Climate change: the role of the infectious disease community. Lancet Infect Dis. 2017;17:1219.
2. Greer A, Ng V, Fisman D. Climate change and infectious diseases in North America: the road ahead. CMAJ. 2008;178:715–722.


Clinical Presentation and Diagnosis of Viral CNS infections

[This post was written by Ahmed Abdul Azim, a senior infectious disease fellow at Beth Israel Deaconess Medical Center]

During the fall and winter season, you are likely to see a few cases of viral meningitis. Even though viral encephalitis is less common, it is important to try to differentiate these clinical entities as a clinician, since they carry different prognoses. (The bulk of this review is adapted from Mandell, Douglas and Bennett’s principles and practice of infectious diseases)1

Cerebral spinal fluid analysis

Before we go any further, let’s briefly review cerebral spinal fluid findings on lumbar puncture for different syndromes:

 WBC(cells/mm3)Primary cellsGlucose(mg/dL)Protein(mg/dL)
Viral50-1000Lymphocytic>45<200
Bacterial1000-5000Neutrophilic<40100-500
Mycobacterial50-500Lymphocytic<4550-300
Cryptococcal/fungal20-500Lymphocytic<40>45

Important points to consider:
·       Bacterial meningitis: 10% of cases have a lymphocyte predominant CSF cell analysis
·       WNV encephalitis: over a 1/3 of patients with WNV encephalitis had neutrophil predominant CSF pleocytosis
·       Enteroviruses: CSF analysis done early in illness course may yield neutrophil predominant pleocytosis in 2/3 of cases – generally will convert to lymphocytic predominant if repeated in 12-24 hours.

Take home point: always interpret CSF within the clinical context in front of you!

  • CSF to serum glucose ratio of < 0.4 is suggestive of bacterial meningitis
  • Traumatic LP may cause elevated CSF protein:
    for every 1000 RBC/mm3, subtract 1 mg/dL protein
  • Traumatic LP may cause elevated CSF WBC:
    for every 500-1000 RBC/mm3, subtract 1 WBC/mm3
  • RBC Adjustment for WBC in CSF = Actual WBC in CSF – (WBC in blood x RBC in CSF/RBC in blood)

Viral meningitis versus encephalitis

Both syndromes often present with a triad of2:
(1) FEVER
(2) HEADACHE and
(3) ALTERED MENTAL STATUS
However, the trick is to explore the history and signs further. Epidemiological clues include:

  • travel history
  • prevalence of disease in the local area
  • occupational exposure
  • animal and insect exposure
  • immunization history
  • underlying immune status

Patients with viral encephalitis: tend to have diffuse cerebral cortex involvement with abnormal cerebral function
Symptoms: altered mental status, motor/sensory deficits, altered behavior and/or personality changes, speech and/or movement disorders

Patients with viral meningitis: DO NOT have diffuse cerebral cortex involvement → cerebral function IS INTACT
Symptoms: headache, lethargy, neck stiffness/pain

Patients with meningoencephalitis: tend to have a combination of meningitis and encephalitis symptoms

Regardless, if a patient has symptoms and/or signs of meningitis or encephalitis, a lumbar puncture can be helpful.

Viral Meningitis – Common Pathogens

Overall, most cases of aspectic meningitis syndromes are caused by viruses

1. Enteroviruses (e.g. Coxsackie, echovirus, other non-polio enteroviruses) – by far the most common cause of viral meningitis/aseptic meningitis3

  • Summer/fall seasons (less commonly in the winter)
  • Clinical manifestations:
    • abrupt onset fever
    • headache
    • vomiting/diarrhea
    • photophobia
    • malaise
    • +/- meningismus
  • Think of enterovirus viral meningitis in patients when rash and/or diarrhea is present
  • CSF analysis done early in illness course may yield neutrophil predominant pleocytosis in 2/3 of cases – generally will convert to lymphocytic predominant if repeated in 12-24 hours4.
  • Take home point: always interpret CSF within the clinical context in front of you!
  • Diagnostics: CSF PCR 86-100% sensitive, 92-100% specific5,6,7

2. Herpes virus simplex viral meningitis – usually caused by HSV-2 >> HSV-18

  • Only accounts for 0.5-3% of viral meningitis/aseptic meningitis cases9
  • Typically mild symptoms
  • 80% with HSV-2 genital lesions/ulcers up to 1 week prior to presenting with viral meningitis
  • Patients with a clinical picture consistent with aseptic meningitis and have HSV isolated in CSF will end up having HSV-2 in 95% of cases. This is a self-limited illness3

3. West Nile Virus – more likely to cause an encephalitis syndrome. Yet, may present with aseptic meningitis or asymmetrical flaccid paralysis10

Viral Encephalitis – Common Pathogens 

A cause is identified in approximately 36-63% of cases10,11

Causes of encephalitis (Most common to least common in US study of patients that met criteria for encephalitis)12:

  • Viruses (70%)
    • Enteroviruses: 25%
    • HSV-1: 24%
    • Varicella zoster virus (VZV): 14%
    • West Nile virus (WNV): 11%
    • EBV: 10%
    • Others: 16%
  • Bacteria (20%)

*In a study of HIV uninfected patients, viruses caused up to 38% of cases, followed by bacterial pathogens at 33%, Lyme disease at 7%, and fungi at 7%. Syphilis was identified as the culprit in 5% of cases, and mycobacterial infections at 5%, while prion disease was responsible for 3% of cases of encephalitis11

1. HSV encephalitis: most common cause of encephalitis in the US (1/250,000 population annually). HSV-1 accounts for greater than 90% of HSV encephalitis in adults13. Fewer than 6% of CSF PCR cases had a “normal” neurological exam14.

  • > 96% have CSF pleocytosis14,15,16
  • Protein is elevated; glucose is normal 95% of the time14,15,16
  • MRI > CT, revealing changes of temporal lobes in ~89% of cases confirmed by CSF PCR15
  • CSF PCR is highly sensitive and specific, with an excellent positive and negative predictive value17
  • If HSV encephalitis is suspected and PCR is negative, repeat HSV PCR testing in 3-5 days
  • HSV PCR remains positive up to 7 days in 98% of cases after onset of symptoms
  • Treatment: IV acyclovir is the treatment of choice; call your nearest ID colleague for help
  • Mortality in acyclovir-treated patients stratified by age group18:
    • 11% in < 2 year olds
    • 22% in 22-59 year olds
    • 62% in > 60 year olds
      (initial level of consciousness strongly predicted mortality16)

2. West Nile Virus encephalitis: transmitted via a mosquito (vector) bite, currently the most common cause of epidemic viral encephalitis nationally19

  • Most are asymptomatic (80%); macular rash in up to 50% of cases20
  •  <1% develop neuroinvasive disease, of which 60% develop encephalitis21
  • High risk patients for neuroinvasive disease: solid organ transplant patients22
  • Clinical presentation21
    • Fever: 70-100%
    • Headache: 50-100%
    • Encephalopathy: 45-100%
    • Cranial neuropathies, mostly facial palsy: 20%
    • Lower motor neuron type lesion: areflexia, hypotonia, preserved sensation
    • Tremors are not uncommon either
  • CSF analysis: pleocytosis (>60% of cases lymphocytic predominant), elevated protein and normal glucose13
  • WNV encephalitis will likely have neuroimaging findings; that is not the case with WNV meningitis
  • MRI much more sensitive than CT. Most common abnormalities seen involving basal ganglia, brain stem and thalamus1
  • CSF diagnosis: WNV-specific IgM in CSF23
  • No established therapy for neuroinvasive disease. Case reports of improvement with IVIG for neuroinvasive disease1
  • Mortality: 12% in severe neuroinvasive disease. Residual neurological changes such as parkinsonism not uncommon
  • Approximately 30% of patients reported fatigue symptoms 6 months to 5 years after infection onset24

Viral Meningoencephalitis – Clinical Approach  

So you are the house officer encountering a patient with 1-2 weeks of progressively worsening fevers, headaches and severe behavioral changes or depressed mental status: what do you do next?

As a standard work up for likely encephalitis in the United States, CSF studies should include1:

  • CSF opening pressure
  • Cell count and differential
  • Protein and glucose (paired with serum glucose)
  • Gram stain and bacterial cultures
  • Initial viral studies to include:
    • HSV-1/2 PCR;
    • VZV PCR;
    • Enterovirus PCR;
    • WNV IgM serology (if seasonally appropriate);
    • CSF viral cultures

Imaging in encephalitis: Magnetic resonance imaging (MRI) of the brain is more sensitive than computed tomography (CT)15. Unless contraindicated, all patients with encephalitis should undergo MR imaging.

  • Temporal lobe and limbic changes → HSV, HHV-619
  • Hemorrhagic strokes and demyelinating lesions → VZV vasculopathy25
  • Subependymal enhancement → CMV ventriculitis25
  • Predominant demyelination → PML (JC virus)

References:

1. Mandell, Douglas and Bennett’s principles and practice of infectious diseases (8th ed. 2015 / Philadelphia, PA : Elsevier)
2. Whitley RJ, and Gnann JW: Viral encephalitis: familiar infections and emerging pathogens. Lancet 2002; 359: pp. 507-513
3. Connolly KJ, and Hammer SM: The acute aseptic meningitis syndrome. Infect Dis Clin North Am 1990; 4: pp. 599-622
4. Gomez B, Mintegi S, Rubio MC, et al: Clinical and analytical characteristics and short-term evolution of enteroviral meningitis in young infants presenting with fever without source. Pediatr Emerg Care 2012; 28: pp. 518-523
5. Rotbart HA: Diagnosis of enteroviral meningitis with the polymerase chain reaction. J Pediatr 1990; 117: pp. 85-89
6. Sawyer MH, Holland D, and Aintablian N: Diagnosis of enteroviral central nervous system infection by polymerase chain reaction during a large community outbreak. Pediatr Infect Dis J 1994; 13: pp. 177-182
7. Ahmed A, Brito F, Goto C, et al: Clinical utility of polymerase chain reaction for diagnosis of enteroviral meningitis in infancy. J Pediatr 1997; 131: pp. 393-397
8. Shalabi M, and Whitley RJ: Recurrent benign lymphocytic meningitis. Clin Infect Dis 2006; 43: pp. 1194-1197
9. Corey L, and Spear PG: Infections with herpes simplex viruses (2). N Engl J Med 1986; 314: pp. 749-757
10. Kupila L, Vuorinen T, Vainionpaa R, et al: Etiology of aseptic meningitis and encephalitis in an adult population. Neurology 2006; 66: pp. 75-80
11. Tan K, Patel S, Gandhi N, et al: Burden of neuroinfectious diseases on the neurology service in a tertiary care center. Neurology 2008; 71: pp. 1160-1166
12. Glaser CA, Gilliam S, Schnurr D, et al: In search of encephalitis etiologies: diagnostic challenges in the California Encephalitis Project, 1998-2000. Clin Infect Dis 2003; 36: pp. 731-742
13. Tyler KL: Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret’s. Herpes 2004; 11: pp. 57A-64A
14. Raschilas F, Wolff M, Delatour F, et al: Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study. Clin Infect Dis 2002; 35: pp. 254-26
15. Domingues RB, Tsanaclis AM, Pannuti CS, et al: Evaluation of the range of clinical presentations of herpes simplex encephalitis by using polymerase chain reaction assay of cerebrospinal fluid samples. Clin Infect Dis 1997; 25: pp. 86-91
16. Whitley RJ, Alford CA, Hirsch MS, et al: Vidarabine versus acyclovir therapy in herpes simplex encephalitis. N Engl J Med 1986; 314: pp. 144-149
17. Lakeman FD, and Whitley RJ: Diagnosis of herpes simplex encephalitis: application of polymerase chain reaction to cerebrospinal fluid from brain-biopsied patients and correlation with disease. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. J Infect Dis 1995; 171: pp. 857-86
18. Whitley RJ, Alford CA, Hirsch MS, et al: Factors indicative of outcome in a comparative trial of acyclovir and vidarabine for biopsy-proven herpes simplex encephalitis. Infection 1987; 15: pp. S3-S8
19. Kramer LD, Li J, and Shi PY: West Nile virus. Lancet Neurol 2007; 6: pp. 171-181
20. Watson JT, Pertel PE, Jones RC, et al: Clinical characteristics and functional outcomes of West Nile Fever. Ann Intern Med 2004; 141: pp. 360-365
21. Sejvar JJ, Haddad MB, Tierney BC, et al: Neurologic manifestations and outcome of West Nile virus infection. JAMA 2003; 290: pp. 511-515
22. Jean CM, Honarmand S, Louie JK, et al: Risk factors for West Nile virus neuroinvasive disease, California, 2005. Emerg Infect Dis 2007; 13: pp. 1918-1920
23. Shi PY, and Wong SJ: Serologic diagnosis of West Nile virus infection. Expert Rev Mol Diagn 2003; 3: pp. 733-741
24. Garcia MN, Hause AM, Walker CM, et al: Evaluation of prolonged fatigue post-West Nile virus infection and association of fatigue with elevated antiviral and proinflammatory cytokines. Viral Immunol 2014; 27: pp. 327-333
25. Gilden DH, Mahalingam R, Cohrs RJ, et al: Herpesvirus infections of the nervous system. Nat Clin Pract Neurol 2007; 3: pp. 82-94

Zoonotic infections

When I was an aspiring Infectious Disease fellow, I marveled at how the ID doctors would come up with diseases that no one else had thought of. How did they do that?

They obtain a detailed patient history. (It’s the ID doctors equivalent of a procedure!)

Contact or exposure to certain animals are associated with certain diseases.

These are examples of some of the questions to ask to ascertain whether your patient has been in contact with specific animals:
– Do you have any pets? Do you have frequent contact with anyone else’s pets?
– Do you have contact with any farm or wild animals?
– What do you do for work (farmer, veterinarian, kennel worker, biologists, etc)?
– What do you do for fun (hunting, fishing, cave explorer, raising chickens, etc)?

I’ve created an easy graphic to give you an idea of some diseases that are associated with different animals your patients might encounter. This is to help you quickly look up which infections you should consider in your differential if your patient reports an exposure to one of these animals.

*This list does not include ALL pathogens. This is just a list of the most common plus others to think about in certain situations. In places outside of North America, this list may look
different.
**This is not intended to take the place of a formal infectious disease consult.
***Use this chart in the context of the clinical presentation. It does not mean you should test for all these infections in every patient, but rather gives you a quick reminder to consider them in your differential.

Was this helpful? Did I miss something? Tell me what you’re thinking with a comment!

References:

1. Centers for Disease Control and Prevention. Healthy Pets Healthy People. http://www.cdc.gov/healthypets/pets/cats.html (Accessed on Feb 23, 2019).
2. Day MJ. Pet-Related Infections. Am Fam Physician. 2016; 94(10):794-802.
3. Goldstein EJC and Abrahamian FM. Diseases Transmitted by Cats. Microbiol Spectr. 2015; 3(5).
4. Chomel BB. Emerging and Re-emerging Zoonoses of Dogs and Cats. Animals (Basel). 2014; 4(3):434-445.
5. Dyer JL, Yager P, Orciari L et al. Rabies surveillance in the United States during 2013. J Am Vet Med Assoc. 2014; 245(10):1111-1123.
6. Boseret G, Losson B, Mainil JG, et al. Zoonoses in pet birds: review and perspectives. Vet Res. 2013; 44(1): 36.
7. Kwon-Chung KJ, Fraser JA, Doering TL, et al. Cryptococcus neoformans and Cryptococcus gattii, the Etiologic Agents of Cryptococcosis. Cold Spring Harb Perspect Med. 2014; 4(7):a019760.
8. National Association of State Public Health Veterinarians, Inc. (NASPHV), Centers for Disease Control and Prevention (CDC). Compendium of measures to prevent disease associated with animals in public settings, 2011: National Association of State Public Health Veterinarians, Inc. MMWR Recomm Rep 2011; 60:1.
9. Kotton CN. Zoonoses from pets other than dogs and cats. UpToDate. Published Jan 2019. Accessed on Feb 23, 2019.

Latent vs. Active TB

Tuberculosis is the leading cause of death globally from an infectious agent. In 2017, an estimated 10 million people developed TB disease and an estimated 1.6 million died1. A recent study demonstrated that <57% of internal medicine housestaff across 7 academic institutions in the U.S. correctly answered 9 out of 10 questions assessing knowledge of assessment and diagnosis of tuberculosis2. This post addresses these questions and to helps clarify latent vs. active TB in a clinical setting.

The primary focus for this blog post is pulmonary TB. Be aware that although the most common presentation of TB is with pulmonary symptoms, TB can present anywhere in the body and sometimes can present without pulmonary symptoms.

But first, definitions.

Definitions

Latent infection – the bacteria lies dormant in the body and does not cause any symptoms, typically tests for latent infection (see later section) will be positive

Active disease – the individual is experiencing symptoms due to the infection in the body, typically with characteristic imaging findings and microbiological confirmation

Primary disease – immediate onset of active disease after infection

Reactivation disease – onset of active disease after a period of latent infection

Extra-pulmonary disease – presence of bacteria outside of the lungs (the primary organ of infection)

Disseminated disease – two or more noncontiguous sites resulting from lymphohematogenous dissemination

Miliary disease – lesions in the lung that resemble millet seeds; seen in some cases of disseminated TB

Step 1: Risk stratification

Risk factors for TB exposure

  • having close contact with individuals who have active tuberculosis (roommates, family, friends, caregivers)
  • living/had lived in a country that is endemic for TB
  • living/working in a prison
  • living/working in a homeless shelter
  • injecting drugs
  • living/working in any other facility/institution that has high rate of TB (hospitals, nursing homes, residential homes for HIV patients) 

*USPSTF gives a grade B recommendation for screening those at increased risk (see list above) for latent tuberculosis infection4

Risk factors for TB reactivation

A. Normal host

  • 5-10% of reactivating TB in a lifetime6,13
  • 50% of that 5-10% is within the first 2-5 years of infection6,13

B. Age – immunity weakens in the elderly

C. Immunosuppression

  • HIV
  • End stage renal disease
  • Diabetes mellitus
  • Lymphoma
  • Corticosteroid or TNF-alpha inhibitor use
  • Cigarette smoking

Step 2: Why is it important to distinguish latent TB from active TB?

The two syndromes are treated completely differently. Latent TB is non-infectious and does not require treatment to prevent progression of disease or transmission to others, but instead to prevent future reactivation. Active TB is infectious and needs to be treated to prevent spread of TB to others. The medications, doses and duration of therapy to treat these syndromes are also different from each other.

Active TB

A. Clinical symptoms

  • fevers/chills, night sweats, weight loss, SOB and/or cough
  • depending on site of TB disease, can have extrapulmonary symptoms (GI, CNS, spine, etc)
  • subacute to chronic onset of symptoms (typically > several weeks)

B. Imaging

  • will typically have active pulmonary abnormalities seen on imaging (this can be any type of abnormality – infiltrates, cavitary lesions, effusions, or solitary nodules)
  • although the most common cause of apical lung scarring is prior TB infection, lung abnormalities DO NOT have to be in the apices of the lungs (they can be anywhere)

Latent TB
(make diagnosis ONLY after you have excluded active TB)

A. Clinical symptoms

  • the patient is asymptomatic (= NO symptoms of active TB)

B. Imaging

  • there is no active lung abnormality on chest imaging
  • (calcified granulomas/nodules or anything that is deemed old, healed scarring is excluded)

*If there are any signs suggestive of active TB, then the patient should undergo active TB evaluation (discussed below). If there is no evidence of active TB, then treatment can be based on latent TB diagnostics (discussed below).

Step 3: Evaluating for TB – diagnostic tests

A. Active TB tests (pulmonary TB)

  • obtain 2-3 sputum samples, ideally at least 8 hours apart, may require sputum induction if patient is not able to cough up sputum.
  • one ideally should be in the morning (highest burden of TB in the morning due to pooling of secretions overnight)
  • obtaining a bronchoscopy sample only counts for one sample
  • send a nucleic acid amplification test (NAAT) on the 1st sputum sample

1. AFB smear – fluorochrome stain of the clinical specimen

  • sensitivity = 67.5% (95% CI, 60.6 to 73.9)8
  • specificity = 97.5% (95% CI, 97.0 to 97.9)8

2. AFB culture – the gold standard test for tuberculosis diagnosis

  • can take up to 6 weeks to grow for solid culture versus ~ 2 weeks for liquid culture

3. PCR = NAAT (nucleic acid amplification test) – this is a DNA test using amplification methods

  • GeneXpert MTB/RIF assay is a brand test that combines the NAAT with rapid test for rifampin resistance sensitivity and specificity are high in pulmonary tuberculosis but is lower when used on specimens other than sputum.
    • sensitivity: 98% (for smear-positive, culture-positive specimens in HIV-negative patients)9
    • specificity: 99%9
  • this test can be run on both AFB smear negative and positive specimens (although sensitivity is lower on AFB smear negative specimens)
  • more specific than the smear because it tests directly for tuberculosis genes, whereas positive AFB smears can be due to non-tuberculous mycobacteria or other acid-fast staining bacteria (i.e. Nocardia)
  • positive result → TB diagnosis
    negative result → does not rule out TB

B. Latent TB tests

1. Tuberculin Skin Test (TST) = Purified Protein Derivative (PPD)

  • intradermal injection of tuberculin material (many different materials available)
  • causes a delayed-type hypersensitivity response in individuals whose immune system has been exposed to TB before
  • positive test = induration at the injection site within 48-72 hours
  • negative test = no induration

Threshold for treatment

TB, tuberculosis; CXR, chest X-ray; HIV, human immunodeficiency virus; IBW, ideal body weight

*individuals who have received the BCG vaccine in the past may also test positive with this test since their immune systems have been exposed to TB via the vaccine (although immunity tends to wane within 10 years if vaccine is administered in infancy)

2. Interferon Gamma Release Assay (IGRA) = QuantiFERON-TB Gold or Plus  OR T-SPOT.TB

  • blood test for detection of cell-mediated immune response to TB antigen
  • not affected by BCG vaccine or BCG treatment
  • 80-90% sensitivity, >95% specificity (sensitivity is diminished in immunocompromised hosts)5
  • the QuantiFERON-TB Gold test is made up of 3 tubes:
    • negative control (everyone should not react)
    • positive control (everyone should react), and the
    • TB antigen that is recognized by CD4 cells
  • **QuantGold-PLUS (a new test) has added a 4th tube with TB antigen that binds to CD8 cells thereby increasing sensitivity of the test12
  • positive test → patient’s blood reacted to the TB antigen and positive control but not the negative control
  • negative test → patient’s blood did not react to the TB antigen but did react to the positive control
  • indeterminate test → patient’s blood did not react to the positive control so test is invalid (this typically happens when the patient is immunocompromised and cannot mount an immune response to the positive control and thus would not react to the TB antigen either – even if they were exposed to TB)

*Indeterminate result DOES NOT mean it is in the middle between negative and positive. It means the test cannot provide a valid result.

*all latent diagnostic tests can cross-react in individuals infected with non-tuberculous mycobacteria (TST more so than the IGRA)

*Neither test is 100% sensitive and specific – if the patient has high pre-test probability for TB exposure and for future TB reactivation, ID physicians will sometimes treat for latent TB despite the negative tests 

Step 4: Treating TB

Treatment is complex and both choice of medication and duration depends on a variety of clinical and microbiological factors. Here is a basic overview of the difference in treatment between latent and active TB.

A. Latent TB (CDC)

*This is a useful calculator to determine the risks and benefits of TB reactivation vs. side effects from treatment in an individual patient. 

            a) Isoniazid – daily for 6 to 9 months

            b) Rifampin – daily for 4 months

            c) Rifapentine and isoniazid – weekly for 3 months

B. Active TB
— depends on susceptibility of bacteria and clinical syndrome
— RIPE therapy is the standard first-line therapy for fully-susceptible pulmonary TB infection with 2 months of all four drugs followed by 4 months of rifampin and isoniazid.

  R = rifampin

  I = isoniazid

  P = pyrazinamide

  E = ethambutol

*Ethambutol can be discontinued if drug susceptibility testing confirms a fully susceptible strain

*Patients with extensive disease e.g. cavitation or who remain smear and/or culture positive at 2 months may require a longer duration of therapy.

Don’t forget to:

  • give daily Vitamin B6 with isoniazid to prevent peripheral neuropathy
  • get baseline eye exam when starting ethambutol to enable monitoring for optic neuritis, particularly in patients with abnormal renal function
  • evaluate for other co-morbidities such as HIV, hepatitis B or C, diabetes or substance use

References:

1. Global Tuberculosis Report 2018: Executive Summary. World Health Organization. Published Sept 2018. Accessed Mar 10, 201

2. Chida N, Brown C, Mathad J, et al. Internal Medicine Residents’ Knowlesge and Practice of Pulmonary Tuberculosis Diagnosis. OFID. 2018; 5(7).

3. Tuberculosis (TB). Centers for Disease Control and Prevention. Available from: https://www.cdc.gov/tb. Accessed Feb 13, 2019.

4. US Preventive Services Task Force. Screening for Latent Tuberculosis Infection in Adults. US Preventive Services Task Force Recommendation Statement. JAMA. 2016; 316(9):962-969. doi:10.1001/jama.2016.11046

5. Lewinsohn DM, Leonard MK, LoBue PA, et al. Official American Thoracic Society/Infectious Disease Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. Clin Infect Dis. 2017; 64(2):111-115. doi: 10.1093/cid/ciw778

6. Horsburgh CR. Priorities for the Treatment of Latent Tuberculosis Infection in the United States. N Engl J Med. 2004; 350:2060-2067. DOI: 10.1056/NEJMsa031667

7. Pai M, Behr MA, Dowdy D, et al. Primer: Tuberculosis. Nature Reviews. 2016; 2:1-23.

8. Mathew P, Yen-Hong K, Vazirani B, Eng RHK, and Weinstein MP. Are Three Sputum Acid-Fast Bacillus Smears Necessary for Discontinuing Tuberculosis Isolation? J Clin Microbiol. 2002; 40(9):3482-3484. doi: 10.1128/JCM.40.9.3482-3484.2002

9. Steingart KR, Schiller I, Horne DJ, Pai M, Boehme CC, and Dendukuri N. Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database Syst Rev. 2014 Jan 21;(1):CD009593. doi: 10.1002/14651858.CD009593.pub3.

10. Zeka AN, Tasbakan S, and Cavusoglu C. Evaluation of the GeneXpert MTB/RIF Assay for Rapid Diagnosis of Tuberculosis and Detection of Rifampin Resistance in Pulmonary and Extrapulmonary Specimens. 2011; 49(12):4138-4141. doi:10.1128/JCM.05434-11.  

11. Menzies D. Use of the tuberculin skin test for diagnosis of latent tuberculosis infection (tuberculosis screening) in adults. UpToDate. Available from: https://www.uptodate.com/contents/use-of-the-tuberculin-skin-test-for-diagnosis-of-latent-tuberculosis-infection-tuberculosis-screening-in-adults#H9. Accessed Feb 13, 2019.

12. QuantiFERON®-TB Gold Plus (QFT®-Plus) ELISA [Package Insert]. Hilden, Germany: Qiagen; 2016.

13. Comstock GW. Epidemiology of tuberculosis. Am Rev Respir Dis. 1982; 125(3 Pt 2):8.

Non-infectious causes of fever

This post is co-written with the guest writer Ahmed Abdul Azim, MD.

Not all fevers are caused by infections.

It is important that every patient presenting with fever is evaluated for an infection….. but what do you do when no infection is found?

thermometer2.png

Why are non-infectious causes of fever important to know?

If a patient is treated for a presumed infectious fever when they don’t have an infection:

  • there is a delay in identifying the correct diagnosis
  • they are exposed to prolonged courses of unnecessary antibiotics

 

Definition of fever

Fever = 38.3°C (101°F) or above1

Pyrogenic agents = substances that can induce a fever.
a) Exogenous pyrogens – external substances that activate our immune system to induce a fever (ex. microbial toxins)
b) Endogenous pyrogens – cytokines that induce fever in our body
(ex. IL-1, IL-6, tumor necrosis factor, IFN-α, ciliary neutrotrophic factor, and likely others)

 

Non-infectious causes of fever:

1. Rheumatologic/autoimmune – activation of immune system that stimulates the production of pyrogenic cytokines
– the cause of ~30% of fevers of unknown origin

a) Adult-onset Still’s disease – younger patients, daily fevers >39°C, rash, arthritis
b) Giant cell arteritis – older patients, vision changes, jaw claudication
c) Others – polyarteritis nodosa, Takayasu’s arteritis, granulomatosis with polyangiitis, etc.

2. Malignancy – tumor cells release pyrogenic cytokines

a) Lymphomas and leukemias – most common; seen in high burden of disease
b) Myelodysplastic syndromes
c) Renal cell carcinoma – ~20% of cases present with fevers
d) Hepatocellular carcinoma or liver metastases
e) Atrial myxomas

3. Drug-induced fever – 3-5% of drug-related adverse reaction in hospitalized patients include fevers6
– typically occurs 7-10 days after drug initiation, but can be as soon as 24 hours and as far away as a few years from drug initiation7
– patients typically appear “inappropriately” well
– eosinophilia (>500/mm3) occurs in 20-25% of patients with drug-induced fevers10
PATHOPHYSIOLOGY:

a) Hypersensitivity reaction – due to activation of T cell immune response by drug, its metabolite, or the formation of an immune complex
– typically occurs ~3-10 days after drug exposure
– typically resolves 72-96 hours after discontinuation of drug (but can be more delayed)
– symptoms will recur immediately upon rechallenge

1) Antimicrobials – most common cause of drug fever
– minocycline, beta-lactams (penicillin-based > cephalosporins10), sulfonamides, nitrofurantoin
2) Anticonvulsants – carbamazepine, phenytoin, phenobarbital
3) Allopurinol
4) Others

DRESS syndrome – a severe type of drug hypersensitivity reaction
(typically occurs 2-6 weeks after drug exposure)

b) Administration-related – typically last <48 hours

1) Vaccines – stimulation of the immune system → release of pyrogenic cytokines
2) Amphotericin B – exogenous pyrogenic agents

c) Pharmacologic action of the drug – transient fever; self-resolving

1) Anti-neoplastic agents – cause severe and rapid tumor cell lysis → release of endogenous pyrogenic agents → inflammatory response (fever)
2) Antimicrobials – cause rapid death of microbes → microbial cell lysis → release of exogenous pyrogenic substances → inflammatory response (fever)
–  ex. Jarisch-Herxeimer reaction in syphilis treatment with penicillin

d) Altered thermoregulation – disturbance of the central hypothalamic thermoregulation function and/or increased heat production

1) Exogenous thyroid hormone
2) Anticholinergic drugs
3) Sympathomimetic agents

cold winter tablet hot

e) Idiosyncratic drug reactions

1) Serotonin syndromes – linezolid, SSRIs
2) Neuroleptic malignant syndrome
– anti-psychotics, dopamine antagonists
3) Malignant hyperthermia syndrome
– inhaled anaesthetics, paralytic agents
4) G-6-PD deficiency – dapsone, primaquine, nitrofurantoin, etc.

4. Other causes

1) Transfusion of blood cells – RBCs, platelets, WBCs
2) Central fevers – fevers due to central thermodysregulation due to CNS damage
– more common with CNS hemorrhage and brain tumors11
– fever onset within 72 hours of sustaining CNS hemorrhage
3) Thromboembolism – typically <102°F
4) Endocrine – thyroid storm; adrenal insufficiency
5) Pulmonary – ARDS, aspiration pneumonitis, cryptogenic organizing pneumonia
6) Intra-abdominal – acute pancreatitis, cholecystitis, mesenteric ischemia

*Non-infectious causes of fevers are diagnoses of exclusion. A patient MUST have an appropriate workup for infectious causes prior to considering any of the non-infectious causes of fever.

*A lot of these diagnoses need to be made based on clinical symptoms and signs and requires a high degree of suspicion.

*Fever is a sign of an underlying inflammatory process.
DO NOT TREAT THE FEVER — TREAT THE UNDERLYING CAUSE.

 

References:

  1. O’Grady NP, Barie PS, Bartlett JG, et al. Guidelines for evaluation of new fever in critically ill adult patients: 2008 update from the American College of Critical Care Medicine and the Infectious Diseases Society of America. Crit Care Med. 2008; 36(4):1330-1349.
  2. Dekker AR, Verheij TJ, and van der Velden AW. Inappropriate Antibiotic Prescription for Respiratory Tract Indications: Most Prominent in Adult Patients. Family Practice. 2015; 32(4):401-407.
  3. Mackowiak PA, Wasserman SS, and Levine MM. A Critical Appraisal of 98.6°F, the Upper Limit of the Normal Body Temperature, and Other Legacies of Carl Reinhold August Wunderlich. JAMA. 1992; 268(12):1578-1580.
  4. Obermeyer Z, Samra JK, and Mullainathan S. Individual Differences in Normal Body Temperature: Longitudinal Big Data Analysis of Patient Records. BMJ. 2017; 359:j5468.
  5. Westbrook A, Pettila V, Nichol A, et al. Transfusion Practice and Guidelines in Australian and New Zealand Intensive Care Units. Intensive Care Med. 2010; 36(7):1138-1146.
  6. Lipsky, BA and Hirschmann JV. Drug Fever. JAMA. 1981; 245(8):851-854.
  7. Mackowiak, PA. Southwestern Internal Medicine Conference: Drug Fever: Mechanisms, Maxims and Misconceptions. Am J Med Sci. 1987; 294(4):275-286.
  8. Patel, RA and Gallagher JC. Drug fever. Pharmacotherapy. 2010; 30(1):57-69.
  9. Johnson DH and Cunha BA. Drug fever. Infect Dis Clin North Am. 1996; 10(1):85-91.
  10. Oizumi K, Onuma K, Watanabe A, et al. Clinical Study of Drug Fever Induced by Parenteral Administration of Antibiotics. Tohoku J Exp Med. 1989; 159(1): 45-56.
  11. Hocker SE, Tian L, Li G, et al. Indicators of Central Fever in the Neurologic Intensive Care Unit. JAMA Neurology. 2013; 70(12):1499-1504.
  12. Porat R and Dinarello CA. Pathophysiology and treatment of fever in adults. In Baron EL, ed. UpToDate. Waltham, Mass.: UpToDate, 2018. [https://www.uptodate.com/contents/pathophysiology-and-treatment-of-fever-in-adults]. Accessed Dec 26, 2018.