P. Witherspoon, Tatarkowska N, Reid F, Anderson JR.
Department of General Surgery, Southern General Hospital, Glasgow, Scotland.
Correspondence to:
Mr John Anderson, Department of Surgery, Southern General Hospital, 1345 Govan Road, Glasgow G51 4TP
E-mail: john.anderson@sgh.scot.nhs.uk
SMJ 2006 51(2): 54
Abstract
A 20 year old fitness instructor was admitted with abdominal pain and rapidly developed severe systemic inflammatory response syndrome and multi-organ dysfunction requiring ventilation and inotropic support. The cause was a histologically early appendicitis. Investigations excluded any underlying immunological or connective tissue disorder.
Intense exercise is known to cause changes in the physiology and function of the immune system. Innate and adaptive immune function, both in cellular numbers and function, has been shown to be impaired. An acute phase response similar to that seen with physical stressors such as sepsis and trauma has also been observed with elevation of pro-inflammatory and anti-inflammatory cytokines. This has led to the ‘open window’ theory of transient immunosuppresion following intense exercise. In this case presented, regular vigorous aerobic exercise was being performed whilst the patient was symptomatic up until 4 hours prior to admission. We propose that exercise induced immunosuppresion and priming of the inflammatory response led to a florid systemic inflammatory response developing and contributed to the rapid progression towards multi-organ dysfunction syndrome.
Keywords: Exercise, Immune, SIRS, Appendix
Introduction
Ever since Larabee noted a significant increase in blood neutrophil concentrations among athletes who ran in the Boston marathon1, it has been known that exercise can induce physiological changes in the function of the immune system. Similarities between those changes induced by exercise and changes induced by other stressors (such as surgery, trauma and sepsis) have been noted and examined from cellular, hormonal and nutritional perspectives2. Potentially serious immunosuppressive effects of intense exercise have been observed in animal models2. Although many human studies have correlated varying degrees of exercise with both immunoprotective and immunosuppressive clinical effects3-5, a direct correlation between intense exercise and adverse clinico-pathological consequences has never been demonstrated. We present a case report of a 20 year old fitness instructor who developed multi-organ dysfunction syndrome and relate it to current opinion on exercise immunology.
Case Report
A 20 year old male was admitted with a 36 hour history of vague central abdominal pain localising to the right iliac fossa. Nausea and bilious vomiting was noted on the day of admission. Systemic enquiry was otherwise unremarkable. There was no significant past medical or drug history. The patient was a fitness instructor and on the day of admission had been instructing his third ‘spin’ (intensive aerobic exercise) class of the day, just 4 hours prior to admission. Examination revealed a pyrexia of 39.5o celsius, blood pressure 90/40mmHg, pulse 90bpm and tachypnoea 30rpm. Abdominal examination revealed mild tenderness in the right upper and lower quadrants. Laboratory investigations revealed a white cell count 3.5 x 109 with normal serum electrolytes and amylase. Chest x-ray was normal. Subsequent blood cultures were negative. An abdominal ultrasound examination revealed a thickened, contracted gallbladder wall but was otherwise normal with no free fluid.
The patient received aggressive fluid resuscitation and broad spectrum intravenous antibiotics (amoxycillin, gentamicin and metronidazole) but continued to deteriorate. He was transferred to the High Dependency Unit where resuscitation was continued with central venous pressure monitoring. Refractory hypotension requiring inotropic support, oliguria and increasing oxygen requirements indicated rapid progression towards Multiple Organ Dysfunction Syndrome (MODS). Arterial blood gases revealed hydrogen ion concentration of 76.8, base excess of -14.2 and a pO2 of 11.14mmHg on an FiO2 of 98%. Eight hours following admission, the patient required ventilation and proceeded to laparotomy. At surgery an inflamed appendix and gallbladder were found and an appendicectomy and cholecystectomy were carried out. Histopathology confirmed a congested appendix with a haemorrhagic tip consistent with early appendicitis. There was evidence of serositis only in the gallbladder.
Following laparotomy, the patient remained ventilated for 6 days secondary to acute lung injury but thereafter made an uneventful recovery. Subsequent investigations excluded any underlying immunological or connective tissue diseases.
Discussion
With intense exercise, various immunological responses have been noted. A predominantly neutrophil leucocytosis occurs during and following intense exercise due to both redistribution of mature cells within the circulation2 and recruitment of immature cells from the bone marrow6. Post-exercise there is a reduction in the total lymphocyte count. The response of these cells to infection, as denoted by in-vitro tests of natural killer, T-cell and neutrophil function, is impaired. A marked increase in stress hormones such as adrenaline, nor-adrenaline, growth hormone and beta-endorphine occurs2. Glutamine, an important ‘fuel’ for lymphocytes, is consumed during exercise2 (the main source is in skeletal muscle). The influence of the resultant ‘glutamine debt’ on lymphocyte function is unclear.
Intense exercise also induces a cytokine response similar to that seen in the systemic inflammatory response (figI). A sequential rise in the pro-inflammatory cytokines TNF-a, Il-1b and Il-6 is seen with compensatory elevation of the anti-inflammatory cytokines Il-10, Il-1ra and TNF-ra7. Concurrent elevated creatine kinase levels has led to the proposal that these changes may be in response to muscle damage. Systemic endotoxaemia, long recognized as a cause of septic disease, has also been observed post-intense exercise and may also contribute to the cytokine response7. Although associated rises in CRP have been noted, the clinical significance of this endotoxaemia is unclear. The main difference is that, although the endotoxaemia and cytokine response occurs, the associated clinical effects of sepsis (such as myocardial depression, pyrexia, MODS) does not2.
These observations have led to the ‘open window’ theory regarding potential clinico-pathological consequences(figII). This theory suggests that there exists a transient period of altered immunity following periods of intense exercise during which bacteria or viruses may gain a foothold, acting essentially as opportunistic infections3. Support for this theory includes the observation that delayed type skin sensitivity tests are impaired post-intense exercise but 2-4 week antibody responses are unaffected5. Epidemiological studies reveal that there is a significantly increased risk of paralysis if exercise of any kind is performed during the paralytic stage of polio2 and animal studies have shown an increase in the mortality of coxsackie B myocarditis from 5% to 50% if the animal is exercised following inoculation with the virus2. In contrast, moderate exercise is thought to enhance immune function with reduced rates of upper respiratory tract infection2 and possible protective effects against bowel and breast cancer being observed5. This apparent ‘dose dependant’ relationship between exercise and immune function has been termed the ‘inverted J’ hypothesis8(figII).
Our fitness instructor developed MODS from mild appendicitis with no explanation for his presentation found from his clinical history or subsequent investigations. He was, however, taking part in strenuous activities during his symptomatic illness. We propose that this activity created an ‘open window’ of transient immunosuppression and primed the inflammatory response for a second hit. The development of appendicitis therefore, instead of inducing a local or mild systemic inflammatory response, resulted in the development of a florid systemic inflammatory response syndrome and rapid progression towards multiple organ dysfunction.
Conclusion
The current understanding of exercise-induced physiological changes in immune function is based on observations in healthy adults and animal models. The implications of this response to disease processes is less clear. In the case presented it is impossible to prove that exercise induced physiological changes in this patients immune function contributed to his illness but no other valid explanation for his presentation has been found. While regular moderate exercise can confer immunological benefits, inappropriate exercise (either in timing, intensity or duration) could have serious and potentially life-threatening consequences. This has implications not only for the training of elite athletes but also for the ‘weekend sportsman’. We suggest further research is warranted in this area.
References
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