FEVER  =  Temperature ≥100.4° F [38.0° C] orally.  If the temp is only 99.8, but the patient gives a history of acute malaise & other convincing symptoms, don’t argue.  Assume it’s a fever.

This posting will address the common presentation: the first few days of acute fever.  Fevers of longer duration, and frank “Fevers of Unknown Origin” (“FUO’s,” however defined), are unusual enough to leave to textbooks.

Before delving into the differential, glance at the other vital signs to make sure they’re not in shock.  Tachycardia up to ±120 is OK if the temperature is elevated.  Eyeball the patient to be sure they’re not in severe distress, & are oriented.  For children, we say “not toxic.”

But suppose a child does seem “toxic,” or an adult appears too weary for your comfort?  You could jump right to blood cultures and lumbar puncture, but there’s a nice trick that obviates the need in the vast majority of cases.  Give a good solid dose of acetaminophen: for adults it’s 1300 mg, for children it’s 20 mg/kg.  Observe them 45 minutes later; if they’re now smiling, joking, running around the waiting room, or complaining about the wait, you’ve avoided a mega-work-up.

Tachypnea suggests pneumonia, but may also be due to fever in-and-of-itself.  Acetaminophen administration can help sort out this parameter as well.

Don’t shy from a one-time high dose of acetaminophen — it has a wide therapeutic index.  The toxic single-dose is 100 mg/kg, but really you need 150 mg/kg [7 gm in adults] to be fatal.  For those seeking lethality, pick a better way.  Tylenol deaths are agonizing.

I’ve seen 3 kids with meningococcal meningitis — fevers dropped nicely with acetaminophen, but behavior remained unchanged.  They got their blood cultures, LP, & empiric antibiotics.  Do the same for adults with severe headache & stiff neck.  If transport will be significantly delayed and you can’t obtain labs, start an IV & give empiric ceftriaxone anyway.  Even IM if necessary.

For the rest of our topic “Fever,” let’s say our patient only looks uncomfortable at the very worst (and if so, acetaminophen makes them feel better).  What’s the diagnosis?

Fever of ≤3 Days’ Duration

For your Differential, look at a human body: virtually any organ can harbor infection.  There’s the brain [meningitis, encephalitis, abscess]; ear (otitis); nose [URI, sinusitis]; mouth [dental abscess, stomatitis]; throat; on down.  Touch on each through history &/or physical exam.

Most sources are obvious.  Nobody has an infected ingrown toenail without mentioning toe pain.  Otitis & pharyngitis won’t be occult either [NEVER diagnose otitis by “red TM” alone].  But hepatitis can present with mere fever and anorexia.  Rashes may go unnoticed.

Pyelonephritis can present without dysuria, but patients usually look somewhat uncomfortable, are nauseated or vomiting, and have some sort of flank or CVA tenderness.  If suspicious, order a simple urinalysis.

Still, many/most patients with acute fever simply complain of malaise and myalgias, with no localizing signs or symptoms.  They have a so-called “Viral Syndrome,” and require no work-up.  Time cures.  Reassurance relaxes.  Advise fluids, antipyretics, rest.  Give a school/work excuse as needed, and instructions to return if not improving in 1-2 days.  Done!

Almost!!!  Some uncommon diseases look like a benign viral syndrome during the first 2-3 days, then turn rapidly lethal.  Think about them.  Please Don’t Miss.  They include:

Malaria  —  Specifically Plasmodium falciparum.  Always inquire about foreign travel.  If a patient just returned from a tropical country within the last 40 days, unless they’d never left a major city, assume they have malaria until proved otherwise.  Even if they took prophylaxis.

The every-other-day fever pattern doesn’t begin for a week, and P. falciparum kills by then, especially healthy tourists without immunity from prior infection (also immigrants who’d returned home to visit, but had been away long enough [a few years] for their immunity to wane).  Order thick & thin smears, & consult I.D.  Disease from its cousin species P. vivax can be delayed up to 3 years from travel, but P. vivax malaria is much milder, never rapidly fatal.  Worry most about travelers back ≤40 days.

Rocky Mountain Spotted Fever  —  We discussed it under “Acute Headache,” but will review.  This rickettsial infection occurs in tick season, April to September.  Remember the highly endemic areas?  North Carolina usually leads the list, followed by OK, TN, AR, MO, & northern counties of MS and AL.  RMSF is rare in CO & the Rockies.

Symptoms begin mild, but include fever & headache.  That alone garners empiric doxycycline in the right place at the right time.  Even for children; even for pregnant women [see Posting #3 “Acute Headache”].  The “spots,” i.e. petichiae, come later, sometimes too late.  Petichiae by definition don’t blanche.  However, in their first few hours, they may appear as blanching macules!  Never rush to label new, discrete, blanching macules in a febrile patient as “viral.”

Meningococcemia  —  This is the same Neisseria meningitidis, gram-negative diplococcus, which causes meningitis, but if it’s only in the blood, the patient may not look sick at first [until shock ensues].  The telltale sign are petichiae, which don’t blanche, unless, as noted, they’re just starting out as blanching macules.  Never rush to label… [see prior paragraph].

Endocarditis  —  The major risk factors include injection drug use, prosthetic heart valve, diseased heart valve, and a past history of endocarditis.  Murmurs may be absent at the onset (except the baseline murmur of a diseased valve).  These patients usually require hospital admission for IV antibiotics pending blood culture results.  This expense might be avoided in flu season, if a nasal swab for influenza antigen is positive [ruling-in an alternative diagnosis for the fever].

Diabetic Ketoacidosis (DKA)  —  Tricky in the undiagnosed Type-1 diabetic, who may first present in DKA due to an infection.  This primarily occurs in children, but is possible at any age.  Your clue is tachypnea, over-and-above that expected for fever, and without the respiratory retractions of pneumonia.  Urine dipstick for glucose & ketones points the way to diagnosis.

AIDS-Related Opportunistic Infections (O.I.’s)  —  Don’t worry about HIV-positive patients with high T-cell counts, especially if they’re on antiviral Tx.  But very tricky to identify an AIDS-related O.I. in patients who don’t know their status.  Click for Clinical clues to undiagnosed HIV infection.  If you suspect this by significant risk factors or clinical findings in someone with a new fever, perform a rapid HIV test.  If positive, or if you can’t do one, send them to the E.D.

Stevens-Johnson / Toxic Epidermal Necrolysis / Toxic Shock (Strep/Staph) —  These horrible afflictions may begin with a 1-2 day prodrome of fever and discomfort.  Unusual skin pain, or muscle pain out of proportion to viral myalgias (especially focal muscle pain), should alert you.  Look for rashes: target lesions, bullae, or sunburn-like erythema.  Mucous membranes are likely involved in SJS/TEN; perhaps oral but also conjunctival (hyperemia) and urogenital (dysuria, retention, vaginal burning).

Fever in the Compromised Host  —  These patients look deceptively well, & can go south fast.  A temp of just 100° F makes me nervous, certainly if their baseline is always normal.  They include:

  • Elderly :  Defined by biologic age more than physical, especially if many comorbidities.  Call it “≥65 y.o.,” but once you yourself are almost there, you’ll probably ratch it up a bit.
  • Debilitated, Malnourished, bad Alcoholics.
  • Active Cancer, especially if on Chemo.
  • Renal Failure, Liver Failure, Adrenal Failure, bad Heart Failure, etc.
  • Immunosuppressive Therapy, esp. post-Organ Transplant.
  • Chronic Rheumatologic disorders, independent of prednisone / immunosuppressives.
  • AIDS ????  Only if not on anti-viral therapy.  Well-controlled HIV patients aren’t at risk.

Of course, compromised hosts are entitled to have a simple virus as much as anyone.  Certainly obtain a dipstick urinalysis; if you find significant (not “trace”) leukocyte esterase and nitrites, and the patient looks well, you can diagnose pyelonephritis, send a culture, and treat empirically.  Otherwise, you might need a same-day CBC and maybe chest x-ray.  If they seem so comfortable that you can’t really punt to an ER, call it “viral” but see them back the next day (TGINF — Thank God it’s not Friday).

Measles (Rubeola)  —  Not usually lethal in this country, but very important to diagnose & report to public health authorities.  Rash usually appears on the 4th day.  Earlier, think of Measles during a known outbreak, if the patient returned from the 3rd World within the last 3 weeks, or if you encounter a patient with fever plus the “3 C’s”:

  • Coryza (runny nose)
  • Conjunctivitis
  • Cough

Look for Koplik’s Spots, tiny white spots on the buccal mucosa opposite the molars (“grains of salt on a red sea”).  Dx Measles by an IgM Antibody.

TO SUMMARIZE:  If a patient presents with ≤3 days of fever, looks well, and complains only of malaise, myalgias, maybe a headache (especially when the fever spikes), and no localizing signs or symptoms, diagnose “Viral Syndrome” & palliate accordingly, unless there’s reason to consider:

  • Malaria (recent foreign travel in rural tropics)
  • Rocky Mountain Spotted Fever (fever + headache, April to Sept., in endemic area
  • Meningococcemia (unexplained macules or petichiae)
  • Endocarditis (IDU, Prostehtic Valve, diseased Native Valve, Hx of Endocarditis)
  • Diabetic Ketoacidosis (tachypnea beyond that expected with fever; urinary glucose & ketones)
  • AIDS (known HIV+ with low T-cells; risk factors; clinical clues on exam)
  • Stevens-Johnson / Toxic Epidermal Necrolysis / Toxic Shock (skin / muscle pain beyond viral myalgias; rashes with target lesions, bullae, or “sunburn,” esp. if mucus membrane involvement)
  • Compromised Hosts
  • Measles

Fever ≥4 Days’ Duration

At this point, we can’t easily call it a simple “Viral Syndrome” any more.  Sometimes patients present at the very tail end of a benign viral illness because they need a work excuse, or the weekend is approaching, or they got nervous that they’re not 100% well.  This is why, for every chief complaint, we always ask, “Is [‘symptom X’] getting better, worse, or staying the same?”

So let’s say our patient has an ongoing fever, with associated constitutional complaints persisting unabated, but not ill enough to send to an ER.  Focal bacterial infections are much more likely at this point.  Even without localizing symptoms, order a:

  • Chest x-ray
  • Urinalysis
  • CBC
  • Liver Function Tests (consider)

Pneumonia is too serious to miss.  Pyelonephritis too, and is not uncommonly occult.  A high white cell count on the CBC, especially if accompanied by a left shift, mandates a search for serious bacterial disease.  The CBC will also identify the unexpected case of leukemia or neutropenia.

Mononucleosis can cause a fever ≥4 days duration, usually with sore throat that converts to just fatigue.  Posterior cervical lymphadenopathy is a clue; splenomegaly is fairly specific but not that common clinically.  The CBC can show “atypical lymphocytes,” and an elevated ALT and AST are also sensitive (but also non-specific).  The “Monospot” test (heterophile antibodies), while highly specific, may be false-negative in the first or even second week of illness.  Definitive testing sooner requires obtaining a specific Epstein-Barr IgM antibody.

If you ever think “mono,” also think Primary (Acute) HIV Infection.  The latter looks exactly the same clinically. This is the “window period,” when the common diagnostic HIV antibody has yet to seroconvert, and the patient is extremely infectious.  Aside from fever, common signs and symptoms include malaise, sore throat, and especially atypical lymphadenopathy (posterior cervical, suboccipital, axillary, or epitrochlear).  Arthralgias, myalgias, and maculopapular rash occur fairly frequently.

Diagnosis is made by an HIV viral load (PCR for RNA); the result must be very high [& often pretty expensive].  HIV can cause false-positive Monospot tests.  If the patient has any risk factors for acquisition in the past month, advise them to abstain from sex until results are back.  If viral load testing isn’t feasible, antibody seroconverts by 1 month 50% of the time, 3 months 95%, & 6 months >99%.  See our discussion in the posting for “Sore Throat-1 and -2”.

Acute Viral Hepatitis (A, B, C, D, E, or other) usually causes anorexia and nausea, but may present with fever alone.  If you ordered LFTs to rule out mono, hepatitis will be an easy pick-up.  Mono is actually another form of hepatitis, along with CMV, human herpesvirus type 6 & maybe 7, toxoplasmosis (a protozoan), syphilis, & others.  All are self-limiting [except during pregnancy].  We’ll discuss viral hepatitis serologies next posting.

Childhood exanthems, which might also present in adulthood, all begin with non-specific fever and malaise 2-5 days before the rash appears.  These include Rubella, Roseola (HHV-6), Rubeola (Measles), Varicella, and B19 Parvovirus (“5th Disease,” “Slapped-Cheek”).  See above for our discussion of Measles.

Some benign febrile illnesses, presumed infectious (usually viral), can last 1-2 weeks without sequelae.  The key here, is that the patient progressively feels better and better.  A patient whose symptoms persist unabated for a week should receive an aggressive work-up.

Occult bacterial infections such as endocarditis, osteomyelitis, perinephric & other abscesses require blood cultures & CTs.  Then there’s a whole host of other infections, some quite serious & equally rare: Typhoid, Rickettsial-like species (ticks), Bartonella (outdoor kittens), Typhus (body lice), Syphilis (sex), Brucella (sheep; raw milk), Listeriosis (raw milk, Mexican cheese), TB … the list is endless.  Let Infectious Disease specialists tailor a work-up based on risks such as exposures and other host factors.

DON’T FORGET non-infectious causes of fever, often more common than microbes, especially for prolonged fever.  Drug fever, venous thrombosis, connective tissue disease, and unidentified cancer are the biggies, though much less common in out-patients than among the hospitalized.

And that’s it for “fever.”  Next time: VIRAL HEPATITIS, because it’s confusing & fun.

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