Case 2: Acute Pharyngitis

Case 2: Acute Pharyngitis (Infection of Jason Hornbuckle)

Jason Hornbuckle is not a happy little boy. For the past 12 hours he has complained of pain when he swallows, has a headache, and has vomited twice. His mother decides to take the seven-year-old to his pediatrician. He is febrile (temperature 40.3 degrees centigrade) with tender, bilateral, cervical lymphadenopathy (enlarged lymph nodes). A Complete Blood Count (CBC) performed on a sample of Jason’s blood reveals: WBC: 14000/mm3, 90% PMNN, 8% lymphocytes, monocytes 2%.  Sedimentation rate: 85/mm3. 

His mother is concerned because the patient is sleeping more than usual.

Summary

Acute bacterial pharyngitis is caused by Group A Streptococcus.  Streptococcus is the most common cause of bacterial pharyngitis in children and accounts for 15 to 30 percent of all cases of pharyngitis in children between the ages of 5 and 15 years. ⁸ Viral pharyngitis is more common than bacterial infection; that is why in order to make an accurate diagnosis, a throat culture must be taken. ¹⁰

A patient will present with swollen and erythematous pharynx, tonsils, and uvula; pain when swallowing, headache, fever, lymphadenopathy, and vomiting. Further, a patient will present with white areas of exudate in the tonsils (Figure 1). A high percentage of neutrophils suggest an acute innate response to the bacterial infection.

Both inflammation and leukocytosis are due to the body’s immunological innate response. Leukocytes such as neutrophils and macrophages enter the site of infection to combat the bacteria. They begin to release various cytokines including: IL-1, IL-6, IL-8, and TNF-alpha, to promote vasodilation and recruit more neutrophils.⁵ However, if the innate response is prolonged the high levels of cytokines will eventually reach the temperature-regulating centers in the pre-optic area of the hypothalamus causing fever.⁵ These increased cytokine levels may also stimulate the liver to produce acute phase proteins, increasing the sedimentation rate.⁵ Enlarged lymph nodes are the result of lymphocyte proliferation. ⁵

On another note, there are several studies that suggest that there is a bidirectional communication between the circadian (sleep-wake) and immune systems. Kruger concluded that sleep is “a local use-dependent process” influenced by cytokines and their effector molecules such as nitric oxide, prostaglandins and adenosine.² IL-1 and TNF-alpha promote non-rapid eye movement sleep and induce symptoms such as sleepiness and fatigue.² (Figure 2) Besides acting on neurons to change input-output properties of the local network, these substances interact with multiple other substances via NFkB activation.²

 

 

   IL-6 is another factor that can affect sleep patterns.  Lorton found that certain IL- 6 levels are negatively related to the amount of nocturnal sleep.³ Exogenous injections of IL-6 into rats caused them profound somnolence and fatigue, suggesting that to have a ‘good-night sleep’ lower levels of IL-6 are required.³ However, with infection IL-6 levels increase dramatically giving the patient symptoms of sleep deprivation, resulting in the need to sleep more.

This interactive brain-cytokine system that alters sleep patterns is critical for an individual to efficiently respond in a coordinated manner to infectious pathogens.³ If activation of this system occurs inadvertently in vulnerable individuals can lead to sleep disturbances and other nonspecific symptoms.

Infectious diseases, as well as physical and mental disorders, are commonly associated with fatigue and sleepiness. As it was previously mentioned, cytokines released to combat the bacterial infection (IL-1, TNF- and IL-6) may induce sleep, explaining the abnormal sleeping pattern.

 

L Case Question

Are there any immunological explanations for the patient’s symptoms?

The patient suffers of a sore throat or acute pharyngitis due to streptococcal infection.  The immune Th₁ cytotoxic response produces inflammatory signs, which includes: pain, heat, redness, swelling, and loss of function that are seen in the area of the pharynx.

Another mechanism used by the body to fight an infection, is fever, due to the WBC production of cytokines and interleukins as IL-1 and IL-6. The pus is produced by the result of dead neutrophils and bacteria. Vomiting is due to the action of the Area Postrema in the medulla that does not have a blood brain barrier (BBB). The excessive sleeping is a result of the actions of cytokines and interleukins in the reticular formation nucleus of Raphe (serotonin) and Nucleus Coeruleus (NE) and the Suprachiasmatic nucleus of the hypothalamus that controls the circadian rhythm. It has been found that fever response is better while sleeping.³

What is the connection between behavior, general symptoms and acute inflammation?

      Jason’s cervical lymph nodes are enlarged because of high proliferation of lymphocytes to fight off a bacterial infection. The enlarged lymph nodes could be compressing against the cervical arteries leading to the brain, hence causing a headache due to diminished blood flow.

 Neutrophils release cytokines that amplify inflammation and cause fever. Thus, the swollen pharynx, tonsils, and uvula are a result of the neutrophil fighting off the infection and the cause of the pain he experiences when swallowing as well as vomiting. The redness seen in the mouth is a typical inflammatory response. The areas of white exudates noticeable on the tonsils indicate plasma with dead and active neutrophils.

 Evidence suggests that there is a bi-directional influence between the immune system and the circadian rhythm, which could explain Jason’s unusual sleeping pattern.⁵ 

What is the mechanism by which fever is induced and what are its benefits in terms of combating an infection?

Fever is a body temperature higher than the normal range of 36.5–37.5 °C. The mechanism that induces fever begins by neutrophil and macrophage release of cytokines: IL-1, IL-6 & TNF, to neighboring endothelial cells. Vasodilatation with increased permeability and edema occurs. The endothelial cells, in response, produce PGI2 which will dilate adjacent capillaries and arterioles; thus, increasing blood flow and allowing more WBCs to localize. With prolonged inflammation, IL-1 & TNF produce a systemic effect. These cytokines act on liver and central nervous system. IL-6 cross the BBB in the hypothalamus, and stimulate the production of local PGI2 which produce a higher temperature set point. Also act on muscle contraction to produce heat.

 This rise in temperature helps fight infections, because pathogens optimal incubation is at 37°C; high temperatures interfere with their invasive functions, making it a hostile environment for pathogens.⁵

What is the mechanism by which the number of circulating white blood cells is increased?

    In the case of Strep infection, the M protein of the surface of the bacteria are recognized by the B cells. This interaction stimulates clonal expansion in the lymph nodes where a single B cell multiplies and secretes the same specific immunoglobulin to opsonize the bacteria and enhance their destruction. Also the release of some cytokines (IL-1, IL-6, IL-8, TNF, IL-23) by macrophages aid in the increase circulating WBC and their extravasations. IL-23 is a pro-inflammatory cytokine and down regulates neutrophils phagocytosis and is a potent stimulator of TH17 CD4. IL-17 stimulates G-CSF in the bone marrow, which stimulates the proliferation of more neutrophils. IL-8 cytokine is a chemo-attractant to neutrophils to the area of infection.

ëPhysical findings

The physical findings include the symptoms:

• Enlarged lymph nodes
• Swollen pharynx
• Tonsillitis with white pup
• Indicating elevated neutrophils
• Fever
• Nausea and Vomiting
• Sore throat while swallowing
• Headache
• Abnormal sleeping patterns

CLINICAL CORRELATIONS

      FEBRILE, HEADACHE, SORE THROAT - Can be alleviated with Aspirin or Tylenol. Prostaglandins are potent mediators of inflammation. The first and committed step in the production of prostaglandins from arachidonic acid is the bis-oxygenation of arachindonate to prostaglandin PGG2. This is followed by reduction to PGH2 in a peroxidase reaction. Both these reactions are catalyzed by cyclooxygenase, also known as PGH synthase. (Cyclooxygenase (COX) is inhibited by the family of drugs known as non-steroidal anti-inflammatory drugs or NSAIDs. Aspirin, ibuprofen, flurbiprofen and acetaminophen (trade name Tylenol) are all NSAIDs.)^7,9

 IMMUNE SYSTEM MOLECULES AND THEIR EFFECTS IN SLEEP PATTERN     Recent studies have shown that sleeping patterns are the result of the actions, in the reticular formation, of Interleukin-1 (IL-1) and tumor necrosis factor (TNF). This molecules promote non-REM sleep under normal physiological condition and also in respond of an inflammatory reaction. The reticular formation has the nucleus of Raphe (Serotonin), Nucleus Coeruleus (Norepinephrine) and the Suprachiasmatic nucleus of the hypothalamus that controls the circadian rhythm. It has been found that fever response is better while sleeping.^3,2
  THE  ERYTHROCYTE SEDIMENTATION RATE

This is a blood test that reveals inflammatory activity in the body. A high sedimentation rate reveals an increase acute phase proteins in the blood produced by the liver. Normal values are 0-10 mm/hr in children, 0-15 mm/hr in men, 0-20 mm/hr in women. This is a direct correlation with an inflammatory response.⁵

aREFERENCES:

1.     Del Mar, C. (1992). Managing sore throat: a literature review. I. Making the diagnosis. http://www.ncbi.nlm.nih.gov/pubmed/1565052. Published April 20, 1992. Accessed May 9, 2012.

2.     Krueger, James. The Role of Cytokines in Sleep Regulation. Curr Pharm Des. 2008: 14(32): 3408–3416.

3.     Lorton, D. (2006). Bidirectional Communication between the Brain and the Immune System: Implications for Physiological Sleep and Disorders with Disrupted sleep. NeuroImmunoModulation. http://www.cfids-cab.org/cfs-inform/Sleep/lorton.etal07.pdf. Published August 6, 2007. Accessed May 8, 2012.

4.     Manzar, MD., & Hussain, ME. (2012). Sleep–immune system interaction: advantages and challenges of human sleep loss model. http://www.frontiersin.org/Sleep_and_Chronobiology/10.3389/fneur.2012.00002/full. Published January 16, 2012. Accessed May 8, 2012.

5.     Murphy, K. Janeway’s  Immuno Biology. 8th edition. Garland Science, Taylor & Francis Group, LLC; NY, 2012.

6.     Marx, J. Rosen's Emergency Medicine: Concepts and Clinical Practice (7th ed.). Philadelphia, Pennsylvania: Mosby/Elsevier; 2010.

7.     Shaikh N, Swaminathan N, Hooper EG. Accuracy and precision of the signs and symptoms of streptococcal pharyngitis in children: a systematic review. J Pediatr. 2012:160(3):487.

8.     Shulman, ST., Bisno, AL., Clegg, HW., Gerber, MA., Kaplan, EL., Lee, G., Martin, JM., & Van Beneden, C. (2012). Clinical Practice Guideline for the Diagnosis and Management of Group A Streptococcal Pharyngitis: 2012 Update by the Infectious Diseases Society of America. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. http://www.ncbi.nlm.nih.gov/pubmed/22965026. Published November 15, 2012. Accessed May 8, 2012.

9.     Tsevat J, Kotagal UR. Management of sore throats in children: a cost-effectiveness analysis. Arch Pediatr Adolesc Med, 1999: 153(7):681.

10.   Wald ER, Green MD, Schwartz B, Barbadora K. A streptococcal score card revisited. Pediatric Emergency Care, 1998: 14(2): 109.