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!
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.
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.
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
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
End stage renal disease
Corticosteroid or TNF-alpha inhibitor use
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.
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)
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)
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
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
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.
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?
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.
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
– 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) 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.
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.
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.
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.
Obermeyer Z, Samra JK, and Mullainathan S. Individual Differences in Normal Body Temperature: Longitudinal Big Data Analysis of Patient Records. BMJ. 2017; 359:j5468.
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.
Lipsky, BA and Hirschmann JV. Drug Fever. JAMA. 1981; 245(8):851-854.
Mackowiak, PA. Southwestern Internal Medicine Conference: Drug Fever: Mechanisms, Maxims and Misconceptions. Am J Med Sci. 1987; 294(4):275-286.
Patel, RA and Gallagher JC. Drug fever. Pharmacotherapy. 2010; 30(1):57-69.
Johnson DH and Cunha BA. Drug fever. Infect Dis Clin North Am. 1996; 10(1):85-91.
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.
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.
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.