Subject: Clinical Pathologic Conference Date: June 25, 2008Topic: Case 1 No. of Pages: 5Transcriber: lucky Editor: Reyia

SEGMENT OF ILEUM AND CECUM o Approx 1.5Liters of clotted blood

The pathologist received a body of a 24- year old male, born in Leyte, whose chief complaint was fever, a non-specific sign and symptom.

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Mesenteric Lymph Nodes

UPON EVISCERATION:

Small Intestine

StomachAbility to penetrate the epithelial cells

Typhoid Bacilli and Water Contamination

Rapidly taken up by macrophages

Thoracic Duct

Carried by macrophages

End of Incubation Period

Non specific signs and symptomso May mimic most of the infectious diseaseso Leukocytopenia

Transient or primary Bacteremiao Brief bacteremic period (not dependent on the

amount of bacilli present) CMI takes longer to develop

Bloodstream

Secondary Bacteremic Phase

Filtered by fixed macrophages in the reticuloendothelial system (RES) o Liver, Spleen

Continuous multiplication of typhoid bacilli in macrophages in the o Liver, Spleen, Bone Marrow

Aggregates of mononuclear cells forming granulomatous

lesions

Disease of the RES CMI mounts a strong

inflammatory response

FINAL ANATOMIC DIAGNOSIS

I. SALMONELLA SEPTICEMIAA. MULTIPLE TYPHOID NODULES

A. EROSION , ULCERATION AND HEMORRHAGES , ILEUMB. LIVERC. BRAIND. KIDNEYSE. COLON F. PANCREASG. ADRENALSH. MESOCOLIC LYMPH NODES

B. POST MORTEM CULTURE OF: ILEAL ULCERS BILE OF THE GALLBLADDER SPLENIC PULP

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Typhoid Nodule

1. Less distinct granuloma2. More Pronounce necrosis3. Erythrophagocytosis

Brain

Adrenal

Pancreas

Spleen

Mesenteric lymph nodes, colon and ileum

Ileum

Meningoencephalitis seizure

Splenomegaly

Hyperplasia of Peyers Patches in the Ileum

Granulomatous lesions may necrotize secondary to occlusion of smaller vessels (microthrombi formation)

Necrotizing lesions progressively coalesce

Ulceration in the intestinal wall (ileum)

Concomitant Schistosoma infection Liver, lungs, pancreas, colon and mesocolic lymph nodes Schistosoma ova

o Delayed type of hypersensitivity reactiono Granuloma formation surrounding the schistosoma

ova which later on replaced by fibrosis

Overloading of the Reticuloendothelial System

Susceptibility to Salmonela Septicemia

Hypotension Bradycardia not improved by fluid challenge

Day 10: Death

Septic Shock

(+) POSITIVE FOR SALMONELLA TYPHI GROWTHC. CHRONIC GRANULOMATOUS INFLAMMATION AND SCHISTOSOMA OVA INVOLVING THE:

LIVER PANCREAS COLON MESOCOLON LYMPH NODES

(+) CONSISTENT WITH SCHISTOSOMA JAPONICUM INFECTION

D. REACTIVE SPLENITIS

II. BRONCHOPNEUMONIA , BILATERAL

III. HEPATOMEGALY (1,750 GRAMS)

CAUSE OF DEATH: SEPTIC SHOCK SECONDARY TO SEVERE SALMONELLA TYPHI BACTEREMIA

Etiologic agent: Salmonella enterica serovar typhi Exclusive human pathogen Gram negative flagellated bacilli Non-sporulating facultative anaerobe Reduces nitrate to nitrite Synthesizes peritrichous flagella when motile Has somatic O, flagellar H, envelope K and surface virulence (Vi) antigens and LPS endotoxin

Pathophysiology and mode of infection:

Symptoms and diagnosis: First symptoms include: loss of appetite, fever, headache, joint pain, sore throat, constipation (or, less

commonly, diarrhea), and abdominal pain and tenderness.

As the illness progresses, fever remains high, and the person may become delirious. Sustained fever is often accompanied by a slow heartbeat and extreme exhaustion.

During the second week and last 2 to 5 days: 10% of infected people get clusters of small, pink spots on the chest and abdomen (Rose spots from typhoid fever)

Intestinal bleeding or perforation occurs in 3 to 5% of infected people (ulcerated peyer’s patches)

Pneumonia may develop

Infection of the gallbladder and liver

At the final stage, a blood infection (bacteremia) occasionally leads to infection of bones (osteomyelitis), heart valves (endocarditis), kidneys (glomerulitis), the genitourinary tract and tissues covering the brain and spinal cord (meningitis).

Infection of muscles may lead to abscesses (collections of pus).

Although the history and symptoms of illness may suggest typhoid fever, the diagnosis must be confirmed by identifying the bacteria in cultures of blood, stool, urine, or other body fluids or tissues.

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Enters blood streamBile ducts

Gallbladder

Stool, urine

Ingestion of S. typhi by host

Apoptosis

Colonizes: Liver Spleen Lymph nodes Peyer’s Patches

In receptor- mediated phagocytosisSubmucosa: Macrophage

Invades through gut Multiplies within mononuclear phagocytic cells

Inflammation and diarrhea

Infect other hostsUlcers, peritonitis

In gut epithelium: Bacteria- mediated endocytosis (BME)

Bile ducts

1. symptoms begin gradually 8 to 14 days after infection. The brassy, nonproductive cough is common. Nosebleed may occur.

2. This Diarrhea may continue, although some people become constipated. In about 10% of infected people, clusters of small, pink spots appear on the chest and abdomen during the second week and last 2 to 5 days. After 2 weeks, intestinal bleeding or perforation occurs in 3 to 5% of infected people.

3. Pneumonia usually results from a pneumococcal infection, although typhoid bacteria can also cause pneumonia.

POSSIBLE SPECIMENS TO BE SUBMITTED FOR CULTURE (BUS)

1. BLOOD-1ST week of infection2. URINE- 2ND week of infection3. STOOL- 3RD week of infection

Chronic carrier state: 1-4% of untreated patients become chronic carriers. Stool carriage is more frequent in people with preexisting biliary abnormalities and these people have a greater

incidence of cholecystitis. Greater risk for carcinoma of the gallbladder 6-fold increase in the risk of death due to hepatobiliary cancer. chronic carriers: defined as individuals who excrete Salmonella for more than 1 year. Some individuals may continue to excrete the bacterium for decades. biliary abnormalities perhaps because S enterica survives in gallstones, hepatobiliary cancer. This may be due to chronic inflammation caused by the bacterium.

DISCUSSION

CASE 1: Salmonella SepticemiaSalmonella typhi

- Flagellated, gram negative bacteria- Causes Self limited food borne and water borne gastroenteritis or typhoid fever- Primarily affects the ileum and colon

Morphology and histology:- Generating blunted villi- Vascular congestion- Mononuclear inflammation- Peyer patchers inv: swelling, congestion, ulceration with linear ulcers, become sharply delineated, plateau like

elevations upto 8 cm in diameter, enlargement of draining mesenteric lymph nodes- Shedding of the mucosa and swollen lymph nodes oval ulcers along the axis of the ileum

Microscopic findings:- Macrophages containing bacteria- RBCs - Nuclear debris

Gross findings:a. Spleen- Enlarged, soft and bulging with uniformly pale red pulp, obliterated follicular markings and prominent sinus

histiocytosis and reticuloendothelial proliferationb. Liver - Small, randomly scattered foci of parenchymal necrosis- Hepatocytes are replaced by a phagocytic mononuclear aggregate typhoid nodules (1.LESS DISTINCT

GRANULOMA 2. MORE PRONOUNCED NECROSIS 3. ERYTHROPHAGOCYTOSIS)

Typhoid fever- Marked by fever and systemic symptoms ( S.typhi)- Protracted disease that is associated with- 1st week: bacteremia, fever and chills - 2nd week: Widespread mononuclear phagocyte involvement with rash, abdominal pain and prostration- 3rd week: ulceration of peyer patches with intestinal bleeding and shock

Pathogenesis:- Salmonella invades intestinal epithelial cells, macrophages- Invasion is controlled by invasion genes that are induced by low tension found in the gut- Genes encode proteins that internalize the bacterium- Intramacrophage growth impt. In pathogenecity, mediated by bact. Genes that are induced by the acid ph within

the macrophage pahgolysosome- Enteric nervous system critical regulator of fluid secretion in the normal gut- Neural reflex pathways increase epithelial fluid secretion in response to enteric pathogens - Bacteremia and systemic dissemination cause proliferation of phagocytes with enlargement of reticuloendothelial

and lymphoid tissues

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Pathophysiology: After ingestion by the host, S typhi invades through the gut and multiplies within the mononuclear phagocytic cells in

the liver, spleen, lymph nodes, and Peyer patches After successfully passing through the stomach, any Salmonella subspecies may be phagocytized by the gut's

intraluminal dendritic cells, causing inflammation that leads to diarrhea. Only the subspecies S enterica causes severe disease in the rest of the body. Its specialized fimbriae adhere to the epithelium that overlies Peyer patches.

They are the primary mechanism for sampling antigens in the gut and initiating response. S enterica enters them via 1 of 3 pathways.

S enterica may convert normally nonphagocytic epithelial cells into bacterially-mediated endocytosis (BME). In BME, Salmonella uses a type III secretion system—macromolecular channels Salmonella insert into eukaryotic cells and intracellular membranes to inject virulence proteins—to inject proteins

SipA and SipC into the epithelial cell. These disrupt the normal brush border and force the cell to form membrane ruffles. The ruffles engulf the bacilli and create vesicles that carry them across the epithelial cell cytoplasm and the basolateral membrane.

In the submucosa, Salmonella enters macrophages via bacteria-triggered pinocytosis or via macrophage receptor–mediated phagocytosis. The intravacuolar environment activates the PhoP/PhoQ regulon, leading to modification of protein and lipopolysaccharide elements of the bacterial inner and outer membranes. Thus, Salmonella resists lysis and decreases host proinflammatory signaling. The bacterium also produces homocysteine to inactivate nitric oxide and enzymes against other microbicides. Finally, with the Vi antigen, a polysaccharide capsule, S typhi and S paratyphi further protect themselves from lysis within the macrophage and from neutrophils and complement without.

In these havens, it multiplies until some critical density is reached. It causes the apoptosis in the macrophages and enters the bloodstream to attack the rest of the body. At this stage, the Vi antigen comes into play. It forms a capsule to protect the bacterium from complement and from phagocytic immune cells.

From blood or from the liver via bile ducts, it infects the gallbladder and reenters the gastrointestinal tract in the bile, spreading to other hosts via stool.

After primary intestinal infection, further seeding of the Peyer patches occurs through infected bile. They may become hyperplastic and necrotic with infiltration of mononuclear cells and neutrophils, forming ulcers that may hemorrhage through eroded blood vessels or perforate the bowel wall, causing peritonitis.

Chronic Schistosomiasis Cercarial penetration to maturation of adult worms Active egg deposition Immunologic process resulting from cumulative deposition of eggs

Miracidium hatches out from excreted egg miracidia infect snails many cercariae released from infected snails people infected by contact with cercariae in water cercariae enters skin & lose their tail to become schistosomulae schistosomulae migrate through tissues, penetrate a blood vessel brought to right heart & lungs they squeeze thru pulmonary capillaries into the systemic circulation portal vessels schistosomule mature in the hepatic portal venules & form pairs worms migrate against portal blood flow & deposit eggs into the mesenteric, vesical and pelvic venulesPathophysio:

- Granuloma formation and hepatic fibrosis- Assoc. with dominant Th2 response with persistence of Th1 helper cells

Septic Shock:Septic shock - due to bacterial toxins thus widespread vasodilation- no loss of intravascular volume- high vasodilation - pooling of venous blood- low cardiac output

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