Diagnosis and the imaging (and laboratory) studies to be ordered largely depend on the patient history, signs and symptoms. If a persistent sore throat with signs of sepsis are found, physicians are cautioned to screen for Lemierre's syndrome.

Laboratory investigations reveal signs of a bacterial infection with elevated C-reactive protein, erythrocyte sedimentation rate and white blood cells (notably neutrophils). Platelet count can be low or high. Liver and kidney function tests are often abnormal.

Thrombosis of the internal jugular vein can be displayed with sonography. Thrombi that have developed recently have low echogenicity or echogenicity similar to the flowing blood, and in such cases pressure with the ultrasound probe show a non-compressible jugular vein - a sure sign of thrombosis. Also color or power Doppler ultrasound identify a low echogenicity blood clot. A CT scan or an MRI scan is more sensitive in displaying the thrombus of the intra-thoracic retrosternal veins, but are rarely needed.

Chest X-ray and chest CT may show pleural effusion, nodules, infiltrates, abscesses and cavitations.

Bacterial cultures taken from the blood, joint aspirates or other sites can identify the causative agent of the disease.

Other illnesses that can be included in the differential diagnosis are:

- Q fever

- Tuberculosis

- Pneumonia

When properly diagnosed, the mortality of Lemierre's syndrome is about 4.6%. Since this disease is not well known and often remains undiagnosed, mortality might be much higher.

Diagnosis is by a swab of the affected area for laboratory testing. A Gram stain is performed to show Gram-positive cocci in chains. Then, the organism is cultured on blood agar with an added bacitracin antibiotic disk to show beta-hemolytic colonies and sensitivity (zone of inhibition around the disk) for the antibiotic. Culture on agar not containing blood, and then performing the catalase test should show a negative reaction for all streptococci. "S. pyogenes" is CAMP and hippurate tests negative. Serological identification of the organism involves testing for the presence of group-A-specific polysaccharide in the bacterium's cell wall using the Phadebact test.

The rapid pyrrolidonyl arylamidase (PYR) test is used for the presumptive identification of group A beta-hemolytic streptococci. GBS gives a negative finding on this test.

Diagnosis is usually based on the symptoms. Medical imaging may be done to rule out complications. Medical imaging may include CT scan or MRI.

"S. pyogenes" infections are best prevented through effective hand hygiene. No vaccines are currently available to protect against "S. pyogenes" infection, although research has been conducted into the development of one. Difficulties in developing a vaccine include the wide variety of strains of "S. pyogenes" present in the environment and the large amount of time and number of people that will be needed for appropriate trials for safety and efficacy of the vaccine.

A throat culture is the gold standard for the diagnosis of streptococcal pharyngitis, with a sensitivity of 90–95%. A rapid strep test (also called rapid antigen detection testing or RADT) may also be used. While the rapid strep test is quicker, it has a lower sensitivity (70%) and statistically equal specificity (98%) as a throat culture. In areas of the world where rheumatic fever is uncommon, a negative rapid strep test is sufficient to rule out the disease.

A positive throat culture or RADT in association with symptoms establishes a positive diagnosis in those in which the diagnosis is in doubt. In adults, a negative RADT is sufficient to rule out the diagnosis. However, in children a throat culture is recommended to confirm the result. Asymptomatic individuals should not be routinely tested with a throat culture or RADT because a certain percentage of the population persistently "carries" the streptococcal bacteria in their throat without any harmful results.

The pus can be removed by a number of methods including needle aspiration, incision and drainage, and tonsillectomy.

Treatment can also be given while a patient is under anesthesia, but this is usually reserved for children or anxious patients. Tonsillectomy can be indicated if a patient has recurring peritonsillar abscesses or a history of tonsillitis. For patients with their first peritonsillar abscess most ENT-surgeons prefer to "wait and observe" before recommending tonsillectomy.

As the symptoms of streptococcal pharyngitis overlap with other conditions, it can be difficult to make the diagnosis clinically. Coughing, nasal discharge, diarrhea, and red, irritated eyes in addition to fever and sore throat are more indicative of a viral sore throat than of strep throat. The presence of marked lymph node enlargement along with sore throat, fever, and tonsillar enlargement may also occur in infectious mononucleosis.

The diagnosis of group A beta-hemolytic streptococcus (GABHS) tonsillitis can be confirmed by culture of samples obtained by swabbing both tonsillar surfaces and the posterior pharyngeal wall and plating them on sheep blood agar medium. The isolation rate can be increased by incubating the cultures under anaerobic conditions and using selective growth media. A single throat culture has a sensitivity of 90–95% for the detection of GABHS (which means that GABHS is actually present 5–10% of the time culture suggests that it is absent). This small percentage of false-negative results are part of the characteristics of the tests used but are also possible if the patient has received antibiotics prior to testing. Identification requires 24 to 48 hours by culture but rapid screening tests (10–60 minutes), which have a sensitivity of 85–90%, are available. Older antigen tests detect the surface Lancefield group A carbohydrate. Newer tests identify GABHS serotypes using nucleic acid (DNA) probes or polymerase chain reaction. Bacterial culture may need to be performed in cases of a negative rapid streptococcal test.

True infection with GABHS, rather than colonization, is defined arbitrarily as the presence of >10 colonies of GABHS per blood agar plate. However, this method is difficult to implement because of the overlap between carriers and infected patients. An increase in antistreptolysin O (ASO) streptococcal antibody titer 3–6 weeks following the acute infection can provide retrospective evidence of GABHS infection and is considered definitive proof of GABHS infection.

Increased values of secreted phospholipase A2 and altered fatty acid metabolism in patients with tonsillitis may have diagnostic utility.

It is hard to differentiate a viral and a bacterial cause of a sore throat based on symptoms alone. Thus often a throat swab is done to rule out a bacterial cause.

The modified Centor criteria may be used to determine the management of people with pharyngitis. Based on 5 clinical criteria, it indicates the probability of a streptococcal infection.

One point is given for each of the criteria:

- Absence of a cough

- Swollen and tender cervical lymph nodes

- Temperature >

- Tonsillar exudate or swelling

- Age less than 15 (a point is subtracted if age >44)

The McIsaac criteria adds to the Centor:

- Age less than 15: add one point

- Age greater than 45: subtract one point

The Infectious Disease Society of America however recommends against empirical treatment and considers antibiotics only appropriate following positive testing. Testing is not needed in children under three as both group A strep and rheumatic fever are rare, except if they have a sibling with the disease.

About 10% of people who present a clinical picture of infectious mononucleosis do not have an acute Epstein–Barr-virus infection. A differential diagnosis of acute infectious mononucleosis needs to take into consideration acute cytomegalovirus infection and "Toxoplasma gondii" infections. Because their management is much the same, it is not always helpful, or possible, to distinguish between Epstein–Barr-virus mononucleosis and cytomegalovirus infection. However, in pregnant women, differentiation of mononucleosis from toxoplasmosis is important, since it is associated with significant consequences for the fetus.

Acute HIV infection can mimic signs similar to those of infectious mononucleosis, and tests should be performed for pregnant women for the same reason as toxoplasmosis.

People with infectious mononucleosis are sometimes misdiagnosed with a streptococcal pharyngitis (because of the symptoms of fever, pharyngitis and adenopathy) and are given antibiotics such as ampicillin or amoxicillin as treatment.

Other conditions from which to distinguish infectious mononucleosis include leukemia, tonsillitis, diphtheria, common cold and influenza (flu).

The heterophile antibody test works by agglutination of red blood cells from guinea pig, sheep and horse. This test is specific but not particularly sensitive (with a false-negative rate of as high as 25% in the first week, 5–10% in the second, and 5% in the third). About 90% of patients have heterophile antibodies by week 3, disappearing in under a year. The antibodies involved in the test do not interact with the Epstein–Barr virus or any of its antigens.

The monospot test is not recommended for general use by the CDC due to its poor accuracy.

For sinusitis lasting more than 12 weeks a CT scan is recommended. On a CT scan, acute sinus secretions have a radiodensity of 10 to 25 Hounsfield units (HU), but in a more chronic state they become thickened, with a radiodensity of 30 to 60 HU.

Nasal endoscopy and clinical symptoms are also used to make a positive diagnosis. A tissue sample for histology and cultures can also be collected and tested. Allergic fungal sinusitis (AFS) is often seen in people with asthma and nasal polyps. In rare cases, sinusoscopy may be made.

Nasal endoscopy involves inserting a flexible fiber-optic tube with a light and camera at its tip into the nose to examine the nasal passages and sinuses. This is generally a completely painless (although uncomfortable) procedure which takes between five and ten minutes to complete.

Antigen detection, polymerase chain reaction assay, virus isolation, and serology can be used to identify adenovirus infections. Adenovirus typing is usually accomplished by hemagglutination-inhibition and/or neutralization with type-specific antisera. Since adenovirus can be excreted for prolonged periods, the presence of virus does not necessarily mean it is associated with disease.

Because of the increased risk of infection, physicians administer oral antibiotics as a prophylaxis after a surgical splenectomy (or starting at birth, for congenital asplenia or functional asplenia).

Those with asplenia are also cautioned to start a full-dose course of antibiotics at the first onset of an upper or lower respiratory tract infection (for example, sore throat or cough), or at the onset of any fever.

A 2014 systematic review of clinical trials does not support using routine rapid viral testing to decrease antibiotic use for children in emergency departments. It is unclear if rapid viral testing in the emergency department for children with acute febrile respiratory infections reduces the rates of antibiotic use, blood testing, or urine testing. The relative risk reduction of chest x-ray utilization in children screened with rapid viral testing is 77% compared with controls. In 2013 researchers developed a breath tester that can promptly diagnose lung infections.

Health care providers distinguish bacterial and viral sinusitis by watchful waiting. If a person has had sinusitis for fewer than 10 days without the symptoms becoming worse, then the infection is presumed to be viral. When symptoms last more than 10 days or get worse in that time, then the infection is considered bacterial sinusitis. Imaging by either X-ray, CT or MRI is generally not recommended unless complications develop. Pain caused by sinusitis is sometimes confused for pain caused by pulpitis (toothache) of the maxillary teeth, and vice versa. Classically, the increased pain when tilting the head forwards separates sinusitis from pulpitis.

A diagnosis can be made from clinical signs and symptoms, and treatment consists of minimizing the discomfort of symptoms. It can be differentiated from herpetic gingivostomatitis by the positioning of vesicles - in herpangina, they are typically found on the posterior oropharynx, as compared to gingivostomatitis where they are typically found on the anterior oropharynx and the mouth.

To minimise the risks associated with splenectomy, antibiotic and vaccination protocols have been established, but are often poorly adhered to by physicians and patients due to the complications resulting from antibiotic prophylaxis such as development of an overpopulation of Clostridium difficile in the intestinal tract.

Chronic cases may be treated with tonsillectomy (surgical removal of tonsils) as a choice for treatment. Children have had only a modest benefit from tonsillectomy for chronic cases of tonsillitis.

There is low or very-low quality evidence that probiotics may be better than placebo in preventing acute URTIs. Vaccination against influenza viruses, adenoviruses, measles, rubella, "Streptococcus pneumoniae", "Haemophilus influenzae", diphtheria, "Bacillus anthracis", and "Bordetella pertussis" may prevent them from infecting the URT or reduce the severity of the infection.

Many cases of croup have been prevented by immunization for influenza and diphtheria. At one time, croup referred to a diphtherial disease, but with vaccination, diphtheria is now rare in the developed world.

The most commonly used system for classifying the severity of croup is the Westley score. It is primarily used for research purposes rather than in clinical practice. It is the sum of points assigned for five factors: level of consciousness, cyanosis, stridor, air entry, and retractions. The points given for each factor is listed in the adjacent table, and the final score ranges from 0 to 17.

- A total score of ≤ 2 indicates "mild" croup. The characteristic barking cough and hoarseness may be present, but there is no stridor at rest.

- A total score of 3–5 is classified as "moderate" croup. It presents with easily heard stridor, but with few other signs.

- A total score of 6–11 is "severe" croup. It also presents with obvious stridor, but also features marked chest wall indrawing.

- A total score of ≥ 12 indicates impending respiratory failure. The barking cough and stridor may no longer be prominent at this stage.

85% of children presenting to the emergency department have mild disease; severe croup is rare (<1%).

The Centers for Disease Control describe protocol for treating sinusitis while at the same time discouraging overuse of antibiotics:

- Target likely organisms with first-line drugs: Amoxicillin, Amoxicillin/Clavulanate

- Use shortest effective course: Should see improvement in 2–3 days. Continue treatment for 7 days after symptoms improve or resolve (usually a 10–14 day course).

- Consider imaging studies in recurrent or unclear cases: some sinus involvement is frequent early in the course of uncomplicated viral URI

Treatment comprises symptomatic support usually via analgesics for headache, sore throat and muscle aches. Moderate exercise in sedentary subjects with naturally acquired URTI probably does not alter the overall severity and duration of the illness. No randomized trials have been conducted to ascertain benefits of increasing fluid intake.

Treatment is usually supportive only, as the disease is self-limiting and usually runs its course in less than a week.