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
  • EMCrit Podcast – EMCrit also has a podcast! Run by Scott Weingart, for those who don’t have time to read.
  • FOAMCast (for the interim also COVIDCast) – an EM podcast run by Lauren Westafer and Jeremy Faust, they provide DAILY high yield updates on COVID-19 literature
  • This Podcast Will Kill You – Two epidemiologists (both named Erin) provide you with an entertaining summary of new COVID-19 knowledge, alongside a recipe for a Quarantini and a Placeborita.

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.

Coccidioides species

Disease: Coccidioidomycosis

Alias: Valley fever, San Joaquin fever

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…).

If you haven’t read the posts on Histoplasma capsulatum or Blastomyces species, go read it now!

This is the 3rd post out of 6 and will focus on our third shapeshifter, Coccidioides species.

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

Morphology(1):

  • This shape shifter differs from others in that it does not shape shift by temperature but resembles other shape shifters in that it exists as a mold in the environment and a spherule (Image) inside the body.
  • Spherules are round, and contain endospores which are uninucleate and have walls and cytoplasmic inclusions
  • Can be mistaken for yeast if only endospores are seen (but endospores don’t bud like yeasts!)

Geography, Reservoir and Mode of Transmission

  • Endemic in southwest of the US and certain arid regions in South America
  • In the US, highest incidence in Arizona and California
  • Reservoir includes: soil (increased during dry periods after rain/storms/earthquakes or excavation work)
  • Mode of transmission: aerogenic
  • Race predilection: Filipino and African Americans at higher risk for disseminated disease (Board favorite!)

Clinical presentation

  • Two-thirds of individuals remain asymptomatic or develop self-limiting respiratory symptoms. When symptomatic → pulmonary involvement in >95% of cases(2)
  • The disease can spread hematogenously to the following extrapulmonary sites: skin, soft tissue, skeleton, CNS (both meninges and spinal cord), eyes, heart, liver, kidneys, and prostate(1)
  • Primary presentation often associated with skin findings (erythema nodosum, erythema multiforme) and rheumatological findings (myalgia, arthralgia)(2)
  • Eosinophilia is often present!
  • Unlike pulmonary nodules in histoplasmosis that often calcify, nodules in coccidiomycosis become small ‘grapeskin’ cavities, and cavities are often thin walled and can be associated with pleural effusions(3)

Diagnosis

Your friendly Infectious disease doctors will always ask for tissue, and if classic spherules are seen in histopathology or culture confirms growth, that’s a slam dunk diagnosis! But we understand that is not always feasible, so in addition to clinical history + presentation, in order of importance:

  1. Tissue/culture
  2. Serology (keeping in mind that it can be false negative very early on in the disease)

Culture:

*Please alert the microbiology lab if you suspect coccidiomycosis and are sending them cultures! (culture needs to be specially handled in the lab due to the risk occupational transmission/infection — just like all dimorphic fungi covered in this review series).

  • Confirms diagnosis, growth usually detected 4-5 days (4)

Histopathology:

  • Presence of endospore-containing spherules is diagnostic (see Image, Morphology)
  • Tissue eosinophilia may be present, and as endospores mature into spherules,
  • Granulomatous reaction predominates

Antigen detection:

  • Urinary antigen not widely used, however urinary histoplasma antigen test could be positive in 50% of cases(4)

Serology:

  • IgM usually becomes detectable within 1-3 weeks therefore negative serology early in the disease doesn’t rule out the disease
  • IgG becomes detectable anywhere between 3rd/4th week to several months after becoming infected. This usually reflects degree of infection and can be used to monitor the disease(4)
  • Increasing titers (or titers >1:32) may suggest dissemination(4)

Molecular methods:

  • No commercially available tests

Management(5)

Pulmonary disease:

  • Mild pulmonary disease: no treatment
  • Asymptomatic nodule/cavity: no treatment
  • Symptomatic chronic cavity: fluconazole/itraconazole (at least) for 12 months

Extra-pulmonary disease:

  • Soft tissue/bone: fluconazole/itraconazole (at least) for 12 months
    (*except for severe disease → Lipid Amphotericin B as an initial therapy for about 3 months)

References:

  1. Walsh TJ, Hayden RT, and Larone DH. Larone’s medically important fungi, 6th edition. ASM Press, 2018.
  2. Salzer HJF, Burchard G, Cornely OA, et al. Diagnosis and Management of Systemic Endemic Mycoses Causing Pulmonary Disease. Respiration. 2018; 96(3):283-301.
  3. Knox KS. Letter to the Editor: Perspective on Coccidioidomycosis and Histoplasmosis. Am J Resp Crit Care Medicine. 2014; 189(6):752-753.
  4. Saubolle MA, McKellar PP, and Sussland D. Epidemiologic, clinical, and diagnostic aspects of coccidiomycosis. J Clin Microbiol. 2007; 45(1):26-30.
  5. Galgiani JN, Ampel NM, Blair JE, et al. 2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Treatment of Coccidioidomycosis. Clin Infect Dis. 2016; 63(6):e112–e146

Blastomyces species

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…).

If you haven’t read the first post on Histoplasma capsulatum, go read it now!

This is the 2nd post out of 6 and will focus on our second shapeshifter, Blastomyces dermatiditis.

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

Morphology(1):

At 25°C-30°C (mold form): septate hyphae with short or long conidiophores where a pear-shaped conidia form at the apex of the conidiophore (has a lollipop-like appearance).
(Image A)

At 37°C (yeast form):
appear as yeast-like cells, thick walled and budding with a broad base
(Image B)

Geography, Reservoir and Mode of Transmission:

  • Endemic in North America (Ohio & Mississippi river valleys and the Great Lakes region)
  • Sporadic cases in Africa and India(2)
  • Reservoir includes: moist soil with decaying vegetative matter, decomposed wood
  • Mode of transmission: aerogenic, skin inoculation

Clinical presentation:

  • Incubation period: 30-45 days (3)
  • Spectrum of clinical disease:
    • Asymptomatic disease – occurs in ~50% of individuals
  • Acute pulmonary blastomycosis – resembles community-acquired pneumonia with variable presentation (infiltrates, consolidation +/- cavitation, reticulonodular patterns, small pleural effusions)(4)
    • Chronic pulmonary blastomycosis – can mimic presentation of TB, lung cancer, and histoplasmosis. Radiographic pattern often is described as alveolar or fibronodular infiltrations, mainly with an upper lobe distribution. Absence of mediastinal lymph node involvement in blastomycosis can distinguish it from Histoplasmosis.(4)
  • Extrapulmonary disease have been described in two-thirds of patients with chronic blastomycosis(3). Most frequent sites: skin, bones and genitourinary system.
  • Patients frequently present with cutaneous lesions without clinically active pulmonary disease.
  • CNS involvement is rare, except in immunocompromised hosts. As many as 40% of AIDs patients who have blastomycosis have CNS disease (mass lesions or meningitis)(5).

Diagnosis:

Your friendly Infectious disease doctors will alwaysask for tissue, and if classic broad-based budding yeast are appreciated in histopathology, that’s a slam dunk diagnosis! But we understand that is not always feasible, so in addition to clinical history + presentation, in order of importance:

  1. Tissue (histopathology, faster visualization, culture will have a long incubation time)
  2. Urine Antigen detection (keeping in mind issues with cross-reactivity as outlined below)

Culture:

*Please alert the microbiology lab if you suspect Blastomycosis 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 series).

  • Most sensitive method, however long incubation time
  • For cutaneous lesions, important to obtain specimen from active leading edge

Histopathology:

  • Forms non-caseating granulomas
  • Classic appearance in clinical samples: Broad-based budding yeast (Image B, morphology)

Antigen detection:

High sensitivity for urine detection (93%) in largest published evaluation(2) but low specificity (79%) due to cross reactivity with Histoplasmosis, Paracoccidioidomycosis and Talaromycosis (previously known as penicilliosis)

Serology:

  • No role in diagnosis because of poor sensitivity and high cross-reactivity(4)

Molecular methods:

  • No commercially available tests

Management(3):

Pulmonary disease

  • Mild to moderate: Itraconazole 6-12 months
  • Moderate to severe: Lipid Amphotericin B for 1-2 weeks followed by →  Itraconazole for 6-12 months

Disseminated disease

  • Mild to moderate: Itraconazole for 6-12 months
  • Moderate to severe: Lipid Amphotericin B for 1-2 weeks followed by →  Itraconazole for 12 months

References:
1. Walsh TJ, Hayden RT, Larone DH. Larone’s medically important fungi, 6th edition, ASM press, 2018.
2. Saccente M and Woods GL. Clinical and laboratory update on blastomycosis. Clin Microbiol Rev. 2010;23:367–381.
3. Chapman SW, Dismukes WE, Proia LA, Bradsher RW, Pappas PG, Threlkeld MG, et al. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America. Clin Infect Dis. 2008 Jun 15;46(12):1801-12
4. Salzer HJF, Burchard G, Cornely OA, et al. Diagnosis and management of systemic endemic mycoses causing pulmonary disease. Respiration; 2018;96:283–301.
5. Pappas PG, Pottage JC, Powderly WG, et al. Blastomycosis in patients with the acquired immunodeficiency syndrome. Ann Intern Med;1992:116

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

Everything You Need To Know About the New ATS/IDSA Community-Acquired Pneumonia Guidelines

The ATS and IDSA recently released the much-anticipated update to the community-acquired pneumonia (CAP) guidelines. The previous version was published back in 2007 and the new guidelines have included some major changes. Here is a rundown of all those changes that you need to know. 

1. Health care associated pneumonia (HCAP) no longer exists

HCAP was an entity created with the 2007 CAP guidelines. It encompassed non-hospital acquired pneumonia in patients who had recent contact with the healthcare system. The recommendation was to treat HCAP with empiric broad-spectrum antibiotic therapy against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (PsA). With this strategy however, we were over-treating a lot of people. This study found that while 30% of all patients hospitalized for CAP received empiric anti-MRSA treatment, only 0.7% of all patients had MRSA pneumonia.

In the new guidelines, HCAP no longer exists. Instead, the guidelines emphasize assessment of risk factors for pathogens such as MRSA and PsA.

2. Treatment is now based on severity of the pneumonia rather than the location of the admitted patient

Prior guidelines differentiated antibiotic recommendations based on patient triage to the floor or the intensive care unit. In the new guidelines, treatment recommendations are based on the severity of the pneumonia, based on a list of criteria:

3. Only obtain blood cultures in severe CAP or if risk factors for MRSA and/or PsA are present

The new guidelines focus on cost-effective use of diagnostic tests.
Outpatient setting: recommend against any diagnostic testing (except for a chest X-ray)
Inpatient non-severe pneumonia: recommend blood cultures and sputum gram stain/culture ONLY if risk factors for MRSA and/or PsA are present
Inpatient severe pneumonia: recommend blood cultures, sputum gram stain/culture, Streptococcus pneumoniae urine antigen, and Legionella urine antigen and PCR/culture
*Legionella diagnostic tests are also recommended in times of an outbreak 

These recommendations are based on literature demonstrating that:

  • Overall prevalence of true positive blood cultures is 1-9% in patients with CAP3-6
  • The majority of true positive blood cultures occur in patients with severe CAP6,7
  • Blood culture results change clinical management in <2% of patients with CAP3,4,6
  • The rate of blood culture contaminants is similar to the rate of true blood culture positives, resulting in unnecessary antibiotics and extended lengths of stay in the hospital3,4,6

4. Procalcitonin should NOT be used in the diagnosis of CAP

Procalcitonin is not a reliable marker for diagnosis of bacterial infections; it has roughly 65-75% sensitivity for detecting bacterial pneumonia8. Consequently, the risk of not treating bacterial CAP due to a low procalcitonin level can lead to poor outcomes. Although there is data to support use of procalcitonin in determining the duration of antibiotics in CAP9,10, the guidelines recommend use only in situations where duration exceeds the recommended 5-7 days.

5. The guidelines recommend use of the Pneumonia Severity Index (PSI) over the CURB-65 for determining need for admission

The argument from the guideline authors is that there is more literature in support for PSI in accurately predicting mortality rather than the CURB-65 score11-14. However, PSI incorporates data that may not be available in all circumstances, and certainly will not be available to the outpatient clinician who is trying to decide whether to admit a patient or not (such as pH, which can only be obtained from an arterial blood gas). So, although PSI may be recommended for use in the emergency department, the CURB-65 will likely remain in use, especially due to its efficiency in the outpatient setting.

6. Algorithm for CAP antibiotic treatment
The meat of the guidelines is the treatment regimens – and there are quite a few changes.

  • 1) Macrolides are no longer recommended as first line therapy in uncomplicated outpatient CAP unless the local streptococcal resistance to azithromycin is <25% (this study shows that most parts of the U.S. have resistance rates >25%).
  • 2) Amoxicillin and doxycycline take the place of macrolides as first line treatment in uncomplicated outpatient CAP.

You may be thinking – “wait, amoxicillin doesn’t even cover atypical pathogens (i.e.  Mycoplasma pneumoniae and Legionella pneumophila)!” This is true. But studies have shown that in otherwise-healthy patients, there was no difference in outcomes among those who received amoxicillin vs. an antibiotic that treats atypical organisms16. Exactly why that is remains unclear, but could be because healthy individuals clear the infection on their own or because the majority of these pneumonias are actually due to a virus, so they would improve with or without any antibiotics 5.

  • 3) In hospitalized patients:
    • Non-severe CAP – only treat empirically for MRSA and/or PsA if the organism has been isolated from the patient’s respiratory tract in the past
    • Severe CAP – treat empirically for MRSA and/or PsA if the patient has any risk factors for MRSA and/or PsA respiratory infection

7. Treat anaerobes only in cases with suspected or proven lung abscess and/or empyema

Empiric treatment of anaerobes in aspiration pneumonia remains controversial, but the new guidelines recommend only treating anaerobes if there is suspicion for or a proven lung abscess and/or empyema.

8. Continue antibiotics for at least 48 hours in patients who are diagnosed with influenza pneumonia

This recommendation is based off the data that influenza infection predisposes to subsequent bacterial superinfections17 and a patient could have both a viral and a bacterial pneumonia at the same time. The guidelines state that if there is significant clinical improvement in 48 hours and no evidence to suggest a superimposed bacterial pneumonia, antibiotics can be discontinued at that time.

9. Duration of antibiotics is based on clinical improvement (but should be a minimum of 5 days)

Gone are the days of prespecified number of days for antibiotic duration. Instead, monitor the patient for signs of clinical improvement.

  • If cultures are not growing MRSA and/or PsA, can stop empiric treatment for MRSA and/or PsA.
  • If clinically improving, stop antibiotics following 48 hours of clinical improvement after a minimum of 5 days. Clinical improvement is determined by resolution of vital sign abnormalities, ability to eat/improved appetite, and normal mentation.

10. Do not use corticosteroids as adjunctive treatment and do not obtain routine follow up chest X-rays

These were not necessarily strategies that I employed prior to the publication of these guidelines, and corticosteroid use in CAP is controversial, but at this time, there is no strong data to support either of these adjunctive management strategies in patients with CAP.

References:

1. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Resp Crit Care Med. 2019; 200(7):e45-e67.
2. Self WH, Wunderink RG, Williams DJ, et al. Staphylococcus aureus Community-acquired Pneumonia: Prevalence, Clinical Characteristics, and Outcomes. Clin Infect Dis. 2016; 63(3):300-309.
3. Chalasani NP, Valdecanas MA, Gopal AK, McGowan JE Jr, and Jurado RL. Clinical utility of blood cultures in adult patients with community-acquired pneumonia without defined underlying risks. Chest. 1995; 108(4):932-936.
4. Corbo J, Friedman B, Bijur P, and Gallagher EJ. Limited usefulness of initial blood cultures in community acquired pneumonia. Emerg Med J. 2004; 21(4):446-448.
5. Jain S, Self WH, Wunderink RG, et al. Community-Acquired Pneumonia Requiring Hospitalization among U.S. Adults. New Eng J Med. 2015. 373:415-427.
6. Lee JH and Kim YH. Predictive factors of true bacteremia and the clinical utility of blood cultures as a prognostic tool in patients with community-onset pneumonia. Medicine (Baltimore). 2016; 95(41):e5058.
7. Waterer GW and Wunderink RG. The influence of the severity of community-acquired pneumonia on the usefulness of blood cultures. Respir Med. 2001; 95(1):78-82.
8. Self WH, Balk RA, Grijalva CG, et al. Procalcitonin as a Marker of Etiology in Adults Hospitalized With Community-Acquired Pneumonia. Clin Infect Dis. 2017;65(2):183-190.
9. Schuetz P, Wirz Y, Sager R, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2017; 10:CD007498.
10. Schuetz P, Wirz Y, Sager R, et al. Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis. Lancet Infect Dis. 2018;18(1):95-107.
11. Aujesky D, Auble TE, Yealy DM, et al. Prospective comparison of three validated prediction rules for prognosis in community-acquired pneumonia. Am J Med. 2005; 118(4):384-392.
12. Marrie TJ, Lau CY, Wheeler SL, Wong CJ, Vandervoort MK, and Feagan BG. A controlled trial of a critical pathway for treatment of community-acquired pneumonia. CAPITAL  Study Investigators. Community-Acquired Pneumonia Intervention Trial Assessing Levofloxacin. JAMA. 2000; 283(6):749-755.
13. Carratala J, Fernandez-Sabe N, Ortega L, et al. Outpatient care compared with hospitalization for community-acquired pneumonia: a randomized trial in low-risk patients. Ann Intern Med. 2005;142(3):165-172.
14. Renaud B, Coma E, Labarere J, et al. Routine use of the Pneumonia Severity Index for guiding the site-of-treatment decision of patients with pneumonia in the emergency department: a multicenter, prospective, observational, controlled cohort study. Clin Infect Dis. 2007;441(1):41-49.
15. Blondeau JM and Theriault N. Application of the Formula for Rational Antimicrobial Therapy (FRAT) to Community-Acquired Pneumonia. J Infect Dis Ther. 2017;5:313.
16. Postma DW, van Werkhoven CH, van Elden LJR, et al. Antibiotic Treatment Strategies for Community-acquired Pneumonia in Adults. New Eng J Med. 2015;372:1312-1323.
17. Metersky ML, Masterton RG, Lode H, File TM Jr, and Babinchak T. Epidemiology, microbiology, and treatment considerations for bacterial pneumonia complicating influenza. Int J Infect Dis. 2012;16(5):e321-331.

A Rash of Beta-Lactam Allergies, Part 3: The Solution

This post is the last in a three-part series covering the management of beta-lactam allergies. Part 1 explained the enormous impact that penicillin allergies have on patient outcomes, while Part 2 discussed the different types of allergic reactions and the potential (or lack thereof) for beta-lactam allergy cross reactivity. This last post will cover the methods used to assess beta-lactam allergies. Let’s jump right in!

There are a variety of strategies that can be used to assess a patient’s beta-lactam allergy, each having their own place in the allergy assessment algorithm. The following will be detailed in this post:

Detailed Patient Interview

Far and away the most important step in assessing a patient’s beta-lactam allergy is a detailed patient interview. An allergy evaluation is recommended by many of the top health organizations in the country, including the Center for Disease Control and Prevention (CDC), National Quality Forum, Infectious Diseases Society of America (IDSA), American Board of Internal Medicine (ABIM), and the American Academy of Allergy, Asthma & Immunology (AAAAI).1 Just a minute or two of questioning the patient can yield an entirely different story than the allergy history in the medical chart. Some common questions I bring up with patients include:

  • How many years ago did the reaction occur?
  • What type of reaction did you have?
  • Do you remember the details of the reaction? Did you have to go to the emergency room?
  • How long after starting the medication did the reaction occur?
  • How was the reaction managed?
  • What happened when the medication was stopped?
  • Have you tolerated other forms of penicillin since the reaction? Have you had Keflex (cephalexin), Augmentin (amoxicillin/clavulanate), or amoxicillin?
    • Using brand names to question patients in this situation is important, as many patients wouldn’t recognize the jumble of letters that is amoxicillin/clavulanate

You can develop your own arsenal of questions to ask patients, but the important part is to talk to them. No further strategies are needed if you can rule out the documented allergy just from a 90-second conversation.

Medication History

The other piece that is absolutely necessary before proceeding is looking through the patient’s medication history yourself. If a patient with a documented penicillin allergy received ceftriaxone without issue on an admission last year, you can go ahead and give full-dose ceftriaxone during this admission if needed. The patient interview and medication history review can rule out >50% of documented allergies in my experience. In these situations, you can skip directly to the last section of this post: allergy re-labelling.

Direct Challenge

In patients with a very low probability of allergic reaction, a beta-lactam antibiotic can usually be given without pause. Situations where you can rule out an allergy based on patient interview or medication history can be “challenged” directly. This means giving the full dose of the preferred antibiotic and monitoring for any adverse effects. Some institutions also give a direct oral amoxicillin challenge with 250-500 mg of amoxicillin once prior to the intended beta-lactam initiation. If the patient can tolerate amoxicillin, any penicillin antibiotic can be given in the future without fear of experiencing an IgE-mediated reaction.

Graded Challenge

When you are not able to completely rule out an allergic reaction, a graded challenge is often the next logical step in hospitalized patients. Graded challenges are used when there is a low probability of an allergic reaction, but there is still a degree of discomfort giving the entire dose up front. In general, 10% of the full dose is given, the patient is monitored closely for 30 minutes, and then the full dose is given if no issues arise. If the patient tolerates these doses, you can rule out immediate hypersensitivity reactions and document the tolerance in the medical record, which will be discussed at the end of this post.

Snippet of graded challenge guideline table from Brigham & Women’s Hospital

Desensitization

In patients who have confirmed or a high probability of severe IgE-mediated reactions to beta-lactams, but a beta-lactam is necessary for treatment, desensitization can be used. The desensitization procedure usually involves at least 12 doses of escalating concentrations of the required medication. This procedure requires incredibly close monitoring, which at most hospitals requires admission to the intensive care unit for administration. If a patient is able to tolerate desensitization, the patient must then begin regularly scheduled doses of the beta-lactam immediately upon the protocol completion. If doses are missed, the patient must be desensitized again. Desensitization does not rule out the allergy. The patient is still considered allergic to that agent, but can tolerate the medication for the course required in that instance.

Penicillin Skin Testing

Penicillin (PCN) skin testing has increased in popularity recently due to its relative ease of use and efficacy at ruling out IgE-mediated allergic reactions. In addition to rescue medications that should be handy just in case (diphenhydramine, methylprednisolone, and epinephrine) the skin test consists of 4 elements:

Initially, a percutaneous puncture test is done on the patient’s forearm with each of the elements and if tolerated, an intradermal test of each is also performed. The entire process generally takes around 45-60 minutes to complete and offers a negative predictive value for penicillin allergies of ~99%.2 Debate has surrounded the cost (both time and materials for the procedure), but multiple studies have now shown penicillin skin testing to be a cost-saving venture.2-5

Penicillin skin testing seems like a no-brainer, carrying the lowest risk of the procedures discussed thus far and its low overall cost for the health system. But in many institutions, it’s unclear who will perform the testing when allergy consultation is not available. In a 2015 survey of 736 infectious diseases providers, 57% responded saying that they do not have local options for skin testing.6 Does your institution?

The people of Twitter have spoken and it resulted in similar responses, with 62% of respondents not having penicillin skin testing available at their institution. Previous studies have reported on the successes of penicillin skin testing performed by allergists,7-9 & many more antimicrobial stewardship programs,10 infectious diseases fellows/physicians,11 nurses,12 and pharmacists.13,14 If you’ve read this far into the post, you likely are interested in allergy skin testing, so I’d implore you to own the process if your institution doesn’t already have skin testing available! ALK provides some excellent instructional videos on their website to guide you through the testing process. Pharmacists aren’t licensed to perform skin testing in all 50 states, but they are in many of them, which this 2019 article did an admirable job exploring.15

Allergy re-labelling

The last fundamental step in navigating beta-lactam allergies is updating the patient’s allergy label. With all of the previous interventions, the allergy documentation can be further described in the medical record, with desensitization being the only intervention that does not rule out IgE-mediated reactions altogether.

Green denotes interventions that can lead to allergy de-labelling. Red denotes the only intervention that should not lead to de-labelling

In an ideal world, inaccurate allergy labels should be removed from the medical record. Unfortunately, this practice often leads to redocumentation of the allergy at a later admission however.16 Many hospitals have integrated innovative ways to improve this repetitive cycle, as seen via providers’ personal experiences here, here, and here. For those without the tech support for any of this functionality though, the best thing to do is to document, document, document.

Summary

The majority of penicillin allergy labels do not belong to patients with true allergies and these unnecessary labels lead to worse patient outcomes. We should all strive for more accurate and detailed allergy documentation in our patients, which all starts with a patient interview. All of the interventions discussed above can be used to remove/relabel a beta-lactam allergy, with the exception of desensitization.

For those looking to learn more, I highly recommend a recent review published in JAMA that goes into further detail on penicillin allergies.17 Make sure to check out the supplementary material too, it has some super helpful resources, including a full allergy toolkit for penicillin skin testing and oral amoxicillin challenges!

Previous posts in this series:

A Rash of Beta-Lactam Allergies, Part 1: The Problem

A Rash of Beta-Lactam Allergies, Part 2: The Education

References

  1. Blumenthal KG, Shenoy ES, Wolfson AR, et al. Addressing inpatient beta-lactam allergies: a multihospital implementation. J Allergy Clin Immunol Pract. 2017;5:616-625
  2. Jones BM, Bland CM. Penicillin skin testing as an antimicrobial stewardship initiative. Am J Health-Syst Pharm. 2017;74:232-7
  3. Mattingly TJ, Meninger S, Heil EL. Penicillin skin testing in methicillin-sensitive staphylococcus aureus bacteremia: A cost-effectiveness analysis. PLoS One. 2019; 14(1):e0210271. doi: 10.1371/journal.pone.0210271
  4. Jones BM, Avramovski N, Concepcion AM, Crosby J, Bland CM. Clinical and Economic Outcomes of Penicillin Skin Testing as an Antimicrobial Stewardship Initiative in a Community Health System. Open Forum Infect Dis. 2019;6(4): ofz109. doi: 10.1093/ofid/ofz109
  5. Rimawi RH, Cook PP, Gooch M, et al. The impact of penicillin skin testing on clinical practice and antimicrobial stewardship. J Hosp Med. 2013;8(6):341-345
  6. Trubiano JA, Beekmann SE, Worth LJ, et al. Improving antimicrobial stewardship by antibiotic allergy delabeling: evaluation of knowledge, attitude, and practices throughout the Emerging Infections Network. Open Forum Infect Dis. 2016; 3(3):ofw153
  7. Blumenthal KG, Wickner PG, Hurwitz S, et al. Tackling inpatient penicillin allergies: Assessing tools for antimicrobial stewardship. J Allergy Clin Immunol. 2017;140:154-161
  8. Macy E, Shu YH. The Effect of Penicillin Allergy Testing on Future Health Care Utilization: A Matched Cohort Study. J Allergy Clin Immunol Pract. 2017;5(3):705-710
  9. Park M, Markus P, Matesic D, Li JT. Safety and effectiveness of a preoperative allergy clinic in decreasing vancomycin use in patients with a history of penicillin allergy. Ann Allergy Asthma Immunol. 2006;97(5):681-687
  10. Leis JA, Palmay L, Ho G, et al. Point-of-Care β-Lactam Allergy Skin Testing by Antimicrobial Stewardship Programs: A Pragmatic Multicenter Prospective Evaluation. Clin Infect Dis. 2017;65(7):1059-1065
  11. Heil EL, Bork JT, Schmalzle SA, et al. Implementation of an Infectious Disease Fellow-Managed Penicillin Allergy Skin Testing Service. Open Forum Infect Dis. 2016;3(3):ofw155
  12. Macy E, Roppe LB, Schatz M. Routine Penicillin Skin Testing in Hospitalized Patients with a History of Penicillin Allergy. Perm J. 2004;8(3):20-24
  13. Chen JR, Tarver SA, Alvarez KS, Tran T, Khan DA. A Proactive Approach to Penicillin Allergy Testing in Hospitalized Patients. J Allergy Clin Immunol Pract. 2017;5(3):686-693
  14. Wall GC, Peters L, Leaders CB, Wille JA. Pharmacist-managed service providing penicillin allergy skin tests. Am J Health Syst Pharm. 2004;61(12):1271-1275
  15. Bland CM, Bookstaver PB, Griffith NC, et al. A practical guide for pharmacists to successfully implement penicillin allergy skin testing. Am J Health Syst Pharm. 2019;76(3):136-147
  16. Rimawi RH, Shah KB, Cook PP. Risk of redocumenting penicillin allergy in a cohort of patients with negative penicillin skin tests. J Hosp Med. 2013;8(11):615-618
  17. Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and management of penicillin allergy: a review. JAMA. 2019;321(2):188-199

A Rash of Beta-Lactam Allergies, Part 2: The Education

This post is the second in a three-part series covering the management of beta-lactam allergies, all to be released on FOAMid over the last few months of 2019. Part 1 explained the enormous impact that penicillin allergies have on patient outcomes. Today we’ll discuss the different types of allergic reactions and the potential for beta-lactam allergy cross reactivity. Let’s jump right in!

Types of Allergic Reactions

The most common way of grouping immune-mediated hypersensitivity reactions is through the Gell & Coombs classification method.2 Using this scheme, there are four types of allergic reaction:

Type I reactions are IgE-mediated reactions and commonly referred to as immediate-type hypersensitivity reactions, since they occur minutes to hours post-exposure to an allergen. Type I reactions include anaphylaxis, angioedema, hypotension, flushing, wheezing, hives, and urticaria.

Both types II and III reactions are IgG-mediated.
Type II reactions, or cytotoxic reactions, include hemolytic anemia, thrombocytopenia, and neutropenia.
Type III reactions are immune complex reactions, and include serum sickness, glomerulonephritis, and arthritis.

Last, but certainly not least, are type IV reactions, which are T-cell mediated.
Type IV reactions are commonly referred to as delayed hypersensitivity reactions, despite Types II, III, and IV all technically being delayed in nature by days to weeks post-exposure to an allergen. A maculopapular rash, interstitial nephritis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome are all considered type IV reactions.

Cross-Reactivity Risk

As discussed in the first post, many recorded antibiotic allergies are not true allergies. But when a patient does actually have a true penicillin allergy, what are the chances that the patient will have a similar reaction to other beta-lactams?

While we would generally avoid penicillins in this situation, other beta-lactams like cephalosporins and carbapenems could potentially be used. Previous studies of 10-25% cross-reactivity between cephalosporins and penicillins were primarily reported prior to 1982, when cephalosporin manufacturing processes were often contaminated with penicillin.12 Since then, the documented rate of cross-reactivity has dropped dramatically, shown in the table below.12

*not all cephalosporins are created equal (see comments below)

Cephalosporins

  • Cephalosporins that do not share a side chain with penicillin have a cross-reactivity risk of <2%
  • Cephalosporins that do share a similar side chain to penicillins (ex. cefoxitin and penicillin) have a cross-reactivity risk that is much higher

Side chain similarities don’t guarantee cross-reactivity, but they do increase the risk above the previously stated 2% threshold

But hold on, I thought the cause of beta-lactam allergies was the core beta-lactam ring that everyone remembers from their undergraduate years?

Penicillin molecule with the highlighted beta-lactam ring

Not so fast. While this plays a part, more recent literature has shown that the R1 and R2 side chains also play a role in the allergy potential of cephalosporins. I have adopted and updated a table from an excellent 2008 review paper by Daryl DePestel and colleagues below.3

In this table, the 3s, 6s, and 7s stand for similar R1 or R2 side chains, as described in the cephalosporin skeleton molecule, also seen below.

  • The R1 side chain is at the 7-position on the cephalosporin molecule and the 6-position on the penicillin molecule.
  • The R2 side chain is at the 3-position, which only differs among cephalosporins and not penicillins.

There are a couple of important clinical points to note from this table. Probably most important for clinical practice is that cefazolin does not share side chains with any other beta-lactam agents. This can have huge consequences on the use of cefazolin in practice, especially when it comes to surgical site prophylaxis and the treatment of methicillin-susceptible Staphylococcus aureus infections, both situations that could use cefazolin as first line therapy.

And while aztreonam is known as a beta-lactam with limited cross-reactivity due to dissimilar side chains, it does actually share a side chain with ceftazidime and the more recently approved ceftolozane (marketed in combination with tazobactam).

Aztreonam & Carbapenems

Speaking of aztreonam, we’ve spent the majority of this post discussing cephalosporin cross-reactivity risk. Now let’s spend a bit of time reviewing the other agents defined in the initial table in this post: carbapenems and aztreonam. Cross-reactivity between these agents and penicillins is minimal, as seen by a number of studies published by an Italian group headed by Antonino Romano and Francesco Gaeta.4,7,9

In their 2013 analysis, they found no patients had an allergic reaction to carbapenems, despite all 204 patients having a well-demonstrated T-cell-mediated hypersensitivity reaction to other beta-lactams (mostly penicillin).7

They went on to look at IgE-mediated hypersensitivity in their 2015 study, which found yet again no cases of hypersensitivity with either carbapenems OR aztreonam this time in a cohort of 212 patients with proven penicillin allergies.4

Then in 2016, they went back to T-cell-mediated hypersensitivity, examining 214 patients with proven reactions to penicillins and testing them against aztreonam. Once again, zero patients reacted to the aztreonam test doses or full dose.9

At this point, you may be questioning if the Italian group ever saw any reactions in their trial outcomes. The last study presented above that showed no reactions with aztreonam though tested more than just aztreonam. They also looked at cephalosporins and saw an 18.7% chance of positive skin testing with aminocephalosporins (cephalexin, cefadroxil, cefaclor).9 If you refer back to the previous cross-reactivity table, you can see that these three agents share a side chain with ampicillin and amoxicillin.

So while side chains play a key role in determining cross-reactivity among cephalosporins, we can be fairly confident that carbapenems and aztreonam are safe to administer in the majority of situations, especially when a non-severe penicillin allergy is documented. This will be covered in more detail in the next (and final) installment of “A Rash of Beta-Lactam Allergies,” coming to you soon!

Other posts in this series:

A Rash of Beta-Lactam Allergies, Part 1: The Problem

A Rash of Beta-Lactam Allergies, Part 3: The Solution

References

  1. Blumenthal KG, Peter JG, Trubiano JA, Phillips EJ. Antibiotic Allergy. Lancet. 2019; 393(10167):183-198
  2. Coombs P, Gell PG. Classification of allergic reactions responsible for clinical hypersensitivity and disease. In: G RR, P.G.H Gell, eds. Clinical aspects of immunology. Oxford, UK: Oxford University Press, 1968; 575-596
  3. Frumin J, Gallagher JC. Allergic cross-sensitivity between penicillin, carbapenem, and monobactam antibiotics: what are the chances? Ann Pharmacother. 2009; 43:304-315
  4. Gaeta F, Valluzzi RL, Alonzi C, Maggioletti M, Caruso C, Romano A. Tolerability of aztreonam and carbapenems in patients with IgE-mediated hypersensitivity to penicillins. J Allergy Clin Immunol. 2015; 135:972-976
  5. Joint Task Force on Practice Parameters; American Academy, American College, & Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010; 105:259-273
  6. Legendre DP, Muzny CA, Marshall GD, Swiatlo E. Antibiotic hypersensitivity reactions and approaches to desensitization. Clin Infect Dis. 2014; 58(8):1140-1148
  7. Romano A, Gaeta F, Valluzzi RL, et al. Absence of cross-reactivity to carbapenems in patients with delayed hypersensitivity to penicillins. Allergy. 2013; 68:1618-1621
  8. Romano A, Gaeta F, Arribas Poves MF, Valluzzi RL. Cross-reactivity among beta-lactams. Curr Allergy Asthma Rep. 2016; 16:24
  9. Romano A, Gaeta F, Valluzzi RL, Maggioletti M, Caruso C, Quaratino D. Cross-reactivity and tolerability of aztreonam and cephalosporins in subjects with a T cell-mediated hypersensitivity to penicillins. J Allergy Clin Immunol. 2016; 138:179-186
  10. Romano A, Valluzzi RL, Caruso C, Maggioletti M, Quaratino D, Gaeta F. Cross-reactivity and tolerability of cephalosporins in patients with IgE-mediated hypersensitivity to penicillins. J Allergy Clin Immunol Pract. 2018; 6(5):1662-1672
  11. Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and management of penicillin allergy: a review. JAMA. 2019; 321(2):188-199
  12. Trubiano JA, Stone CA, Grayson ML, et al. The 3 Cs of antibiotic allergy-classification, cross-reactivity, and collaboration. J Allergy Clin Immunol Pract. 2017; 5(6):1532-1542