CPC #4: A Case of the Swollen Organ

1. CPC #4: A Case of the Swollen Organ Bridging the Gap. Where Clinical and Basic Sciences Meet Louisa Balazs, MD, PhD Associate Professor of Pathology Maximiliano Arroyo, MD Fellow, Cardiovascular Diseases Karl T. Weber, MD Professor of Medicine

2. Undaunted by the heat and humidity offered on this Wednesday, January, 14, 1970, the streets of São Paulo were filled with confident rhetoric about Brasil’s football team. Despite its absence from the finals of the World Cup in 1966, this year’s team was felt to have an excellent chance to again reign as champion.

3. The Cup would be held in Mexico this June and Mario Zagalo, former member of the 1958 and 1962 championship teams, would serve as coach. And this time around there would be Pelé, who because of injury had missed his team’s 3–1 victory over Czechoslovakia on June 17, 1962, in Santiago. Busy rounding on the medical service of this famous University hospital was Nick de Carvelho, second-year resident in internal medicine. As usual, the ward was filled to capacity and his patients represented a remarkable diversity of illnesses.

4. This morning 3 patients in particular posed several mysteries that he wished to solve. Mr. H., a 53-year-old businessman, was convalescing with strict bed rest after his myocardial infarction (MI) 14 days earlier and which had been complicated by acute pulmonary edema, but which had resolved spontaneously.

5. Miss F., a 16-year-old, who presented to the emergency room with a history of painless edema of the left palpebrae and periocular tissue (Figure) followed by malaise, fever, facial edema and signs and symptoms of heart failure. A presumptive diagnosis of acute Chagas’ disease with Trypanosoma cruzi infestation had been made.

6. Mr. S., a 35-year-old agricultural worker who just yesterday had been bitten on the hand when he startled a viper in the weeds.

7. The snake was likely Bothrops jararaca, the most frequent venomous species seen in southern Brasil. This included Rio Grande do Sul, São Paulo and Rio de Janeiro.

8. At the Hospital Vital Brasil of the Instituto Butantan, venomous snakebites have long posed a serious health problem. From 1902–1945, there were 6001 reported cases with B. jararaca accounting for 52% while between 1954–1965 a total of 15,709 cases were seen and of those poisonous, 36% were related to this viper.

9. Mr. S. had presented to the emergency room several hours after the bite with a painful and swollen hand. Unlike more serious bites Nick had seen, there was no bleeding from the gums, nose, or internal organs. Antivenin had been administered—a treatment that had substantially reduced mortality from such bites.

10. As Nick prepared for rounds with his attending, he pondered about similarities between these three cases. He reflected back on lectures given during sophomore year pathology, where the initial exudative and inflammatory phases of wound healing were noted to be followed by cicatrization.

11. And while etiologic factors were distinctive for each entity, the same early phases of healing that eventuated in a swollen organ had to be operative. Was this fanciful or was Nick right to correlate the inflammation-healing paradigm in each of these disparate entities?

12. Mr. H: Acute Myocardial Infarction Myocardial Interstitial Edema with increase in wall stiffness Pulmonary Edema Increase in pulmonary venous pressure

13. Miss.FChagas Myocarditis • Major Cardiovascular manifestation is an extensive myocarditis that typically becomes evident years after the initial infection. • Acute: During this phase it can be transmitted to humans through the bite of a reduviid bug. It harbors the parasite in the GI tract.

14. The bug often bites the person around the eyes and later infects when parasites in the animal’s feces gain entry through abraded skin or conjunctivae. Occasionally this results in unilateral periorbital edema and swelling of the eyelid, termed the Romaña sign, whereas entry through the skin my result in a lesion called chagoma

16. Metacyclic trypomastigotes are effective forms of T. cruzi that pass from the insect's hindgut in the fecal matter and burrow into the skin, either through the bite site or skin abrasions. • After metacyclic tryps pass through the skin, they briefly travel in the blood stream and then colonize muscle and neuron tissue, areas less vulnerable to attack, where they encyst and form amastigotes

17. Mr.SSnake Bite • Bothrops is distributed in most parts of Latin America and the southern parts of the Caribbean area. The genus holds a variety of poisonous species.

18. Inflammation

19. Snake Venom and ACE-I • The venom of the Bothrops jararaca induces systemic vasodilatation. Ferreira’s, et al. search for the active component of the venom led to the discovery of bradykinin-potentiating factor. • Bradykinin-potentiating peptides prevent the conversion of BK into inactive metabolites, therefore, were inhibitors of kininase II. They also would prevent the conversion of Angiotensin I to Ang II, therefore, considered ACE inhibitors. • Inhibition of ACE was subsequently found to also reduce the degradation of other substances, including substance P and enkephalins, which are mediators of inflammation. Weber KT, Wound Healing in Cardiovascular Disease, 1995

20. Weber KT, Wound Healing in Cardiovascular Disease, 1995

21. Seaweed and Chemical Mediators of Inflammation • The release of BK and Prostaglandins is associated with immediate sustained response in vascular hyperpermeability and accompanies the injection of a polysaccharide derivative of seaweed, Chondrus crispus, (CARR). Weber KT, Wound Healing in Cardiovascular Disease, 1995

22. Weber KT, Wound Healing in Cardiovascular Disease, 1995

23. An ACE inhibitor will attenuate kininase II activity and thereby increase local concentrations of BK and potentiate its effects. • Captopril increased CARR-induced paw edema; the same was true for kininase II inhibitor phenanthroline. Weber KT, Wound Healing in Cardiovascular Disease, 1995

24. Conclusions • The heart, skin and other tissues respond to injury and infection in a similar way. • BK is an essential component of the reaction seen in the heart and skin following seaweed injection, infection or infarction. • BK causes initial vasodilatation, followed by vascular hyperpermeability interstitial edema Swollen Organ

25. Inflammation Pathomechanism and physiology

26. Stimuli for acute inflammation • Infections (bacterial, viral, parasitic) • Trauma (blunt, penetrating) • Physical and chemical agents • Tissue necrosis • Foreign bodies • Hypersensitivity reactions

27. Changes in vascular flow and caliber • Vascular dilation (effect of histamine, nitric oxide on smooth muscle), blood flow increased • Increased permeability, outflow of protein rich fluid (vasoactive amines, bradykinin) • Stasis • Leukocyte adhesion and migration

28. Vascular Leakage • Reduced intravascular and increased extra vascular osmotic pressure -EDEMA • Formation of intravascular gaps • Direct endothelial injury • Leukocyte dependent injury • Increased transcytosis • New blood vessel formation

29. Formation of endothelial gaps • Effects venules (20-60 microm) • Elicited by: histamine, bradykinin, leukotrienes, neuropeptide substance P • Phosphorylation of contractile and cytoskeletal proteins • Contraction of endothelial cells and separation of intercellular junctions

30. Insect bite, increased blood flow (rubor)

31. Insect bite, edema

32. Acute dermatitis

33. Acute myocardial infarct

34. Interstitial edema, acute myocardial infarct

35. Outcome of acute inflammation • Resolution (clearance, replacement, normal function) • Pus formation (precedes healing) • Fibrosis (healing, loss of function) • Progression (chronic inflammation, followed by healing)

36. Myocardial infarct, cellular reaction

37. Insect bite - chronic phase

38. Myocardial fibrosis

39. In February, 1901, the Institute Butantan officially opened with Dr. Vital Brazil, a pioneer in the development of serotherapy against snakebite and the specificity of antivenins, named its director. By 1970, chemical mediators of inflammation following snakebite or subcutaneous injection of foreign substance (e.g., seaweed) had received considerable interest.

40. This included the famous laboratory of Rocha e Silva in the Department of Biochemistry and Pharmacodynamics, Instituto Biologico, São Paolo.

41. Silva’s laboratory found venom extract caused a gradual contraction of guinea pig ileum compared to rapid contraction by histamine. He therefore named this substance bradykinin.

42. Edema in the heart, as seen after infarction or trypanosome infestation, can account for abnormal myocardial stiffness. A bradykinin potentiating factor is present in snake venom. It is known today as a kininase II inhibitor (alternatively an angiotensin I converting enzyme inhibitor) and was reported by Ferriera from São Paolo in 1970.

43. Indeed, the heart, skin and other tissues respond to injury and infection in a rather similar fashion. Depending on the nature of the stimulus, chemical mediators of inflammation, such as histamine, serotonin, bradykinin and prostaglandins, are released. Bradykinin is central to the response seen in the heart and skin following infarction, infection or seaweed injection. Its initial vasodilatory properties are followed by vascular hyperpermeability with interstitial edema—the swollen organ.