Chapter 39 – Bacterial, Parasitic, and Fungal Infections of the Liver in Children




Abstract




Both systemic and local infections caused by bacterial, fungal, and parasitic agents may cause significant hepatic dysfunction. This chapter will attempt to delineate clinical syndromes caused by some of these organisms in the pediatric patient.





Chapter 39 Bacterial, Parasitic, and Fungal Infections of the Liver in Children


Donald A. Novak , Gregory Y. Lauwers , and Richard L. Kradin



Introduction


Both systemic and local infections caused by bacterial, fungal, and parasitic agents may cause significant hepatic dysfunction. This chapter will attempt to delineate clinical syndromes caused by some of these organisms in the pediatric patient.



Bacterial Infections



Associated Liver Disorders



Hyperbilirubinemia Associated with Sepsis

While jaundice in association with bacterial sepsis may occur in adults, it appears to be significantly more common during infancy. Historically, infections of the urinary tract predominate but sepsis originating from other sites may contribute [1]. Accordingly, gram-negative bacilli, and particularly Escherichia coli, are responsible for the majority of cases, although gram-positive organisms have been associated. Abnormal liver chemistries are found in approximately 50% of premature neonates with gram-negative bacteremia [2]. Clinical and laboratory manifestations are primarily those of the underlying disease state. Hyperbilirubinemia may be marked, with the direct fraction predominant. Alkaline phosphatase levels are often elevated, while serum aminotransferases remain normal or minimally increased. Hepatic biopsy usually demonstrates canalicular cholestasis, with minimal evidence of hepatocyte damage or inflammatory response (Figure 39.1). On occasion, the biopsy may demonstrate prominent acute cholangitis with portal bile ductular proliferation, pathologic changes often seen in large bile duct obstruction. In these cases, the possibility of large duct obstruction must be excluded by ultrasound or endoscopic retrograde cholangiopancreatography (ERCP). Jaundice resolves with appropriate treatment of the underlying infection; duration of jaundice may vary from several days to several weeks. While the pathophysiology of sepsis-related cholestasis has not been fully elucidated, endotoxin, which is known to diminish bile flow and provoke cholestasis, may play a role. Other inflammatory mediators with potential roles include tumor necrosis factor, the leukotrienes, and interleukin-1. Fatty liver has also been reported in conjunction with gram-negative sepsis [3].





Figure 39.1 Sepsis. Perivenular hepatocytes demonstrate dilated canaliculi containing bile. The sinusoids contain a mixed inflammatory infiltrate associated with Kupffer cell hyperplasia.



Pyogenic Hepatic Abscess

Pyogenic liver abscess (PLA) continues to be a significant source of morbidity, if not mortality, in the pediatric population. Although early reports quoted an incidence of three in 100,000 hospital admissions (prior to 1977) [4], recent studies have suggested an increasing rate of PLA, conditionally attributed to improved overall survival of immunocompromised patients. Current rates seem to be approximately 10–25 in 10,000 in the developed world, with higher rates noted in less developed nations [5]. Concomitantly, mortality has fallen from older estimates of 36% to 15% in recent series; mortality rates are higher in those with multiple abscesses [6]. Patients at risk include those with impaired host defenses; chronic granulomatous disease and leukemia are commonly noted in children. Approximately 50% of children with PLA are under the age of six.


Clinical manifestations of PLA in children are non-specific but commonly include fever, abdominal pain, right upper quadrant tenderness and hepatomegaly [4]. Multiple abscesses, as well as those caused by gas-forming organisms, may present in a more fulminant manner. Ruptured abscesses presenting with abdominal pain and septic shock are also associated with higher mortality rates. Laboratory findings may include elevation of the erythrocyte sedimentation rate (ESR), leukocytosis, anemia, and hypoalbuminemia. Serum aminotransferase and bilirubin values may be variably elevated; in series of adult patients, serum alkaline phosphatase values are more reliably increased. Diagnosis of PLA is generally made via a high index of clinical suspicion in conjunction with appropriate imaging techniques. Approximately 75% of PLA are located in the right lobe of the liver. In a 1989 review of 109 children with PLA, CT and angiography were noted to be the most sensitive techniques, followed by ultrasound and radioisotope scanning [7]. Ultrasound, typically the first modality employed, with a sensitivity as high as 96% reported, may miss lesions in the dome of the liver. Lesion detection can also be made with MRI. All techniques presently available are hampered by a lack of specificity. As the differential diagnosis of intrahepatic cysts includes abscess caused by non-pyogenic organisms, congenital cysts, tumor with central necrosis and/or hemorrhage, as well as vascular malformation, specific diagnosis generally requires lesion aspiration with subsequent gram stain and culture. In appropriate clinical situations, serology for hydatid disease and Entamoeba histolytica should be considered prior to aspiration. Percutaneous drainage under CT or ultrasound guidance is often feasible, particularly in the case of large, solitary, superficial lesions (Figure 39.2). As opposed to adults, in whom gram-negative bacilli predominate, Staphylococcus aureus is the predominant etiologic agent in children. This may reflect the significant number of immunocompromised patients in pediatric series of PLA. Enteric gram-negative bacteria, predominantly E. coli and Klebsiella sp., account for approximately 31% of PLA in recent series, while anaerobic organisms are causative in at least 15% [8]. Other organisms found include Nocardia asteroides, Streptococcus sp., Yersinia sp., Salmonella sp., Campylobacter jejuni, Pasturella multocida, and Legionella pneumophila, among others to be discussed later in the chapter. Infections may be mixed. Tuberculosis is a rare cause of hepatic abscess as is actinomycosis; fungal and parasitic infections are described below [9].





Figure 39.2 Pyogenic liver abcess by CT. (A) Before drainage showing abscess cavities (arrows). (B) After percutaneous drainage, with the open arrow indicating the drainage catheter.


The etiology of PLA is variable. Adult series demonstrate a preponderance of patients with pre-existing biliary tract disease, in whom PLA develops as a consequence of cholangitis. Traumatic injury to the liver may result in PLA, as may sepsis. Extension from contiguous sites of infection may occur, such as after a ruptured appendix. Predisposition by prior infection with Toxocara canis has also been hypothesized [10]. In children, altered host defenses seem to play an important role [11], as may portal vein bacteremia from intra-abdominal infectious processes (e.g., appendiceal abscess, abscess secondary to ingested foreign body, and inflammatory bowel disease). Occurrence of PLA has also been associated with the use of umbilical venous catheters in the newborn population. Approximately one-half of patients in adult series had no evident etiology.


Successful therapy of PLA is contingent upon rapid and accurate diagnostic efforts. Drainage and appropriate antibiotic coverage continue to be the mainstays of therapy. Initial antibiotic coverage should be broad spectrum, including agents effective against gram-positive aerobes, gram-negative bacilli, and anaerobic organisms. Subsequent therapy is dictated by culture results. Percutaneous drainage is indicated in those patients in whom lesions are accessible under CT or ultrasound guidance [12].


Catheters placed via these techniques are generally left in place until abscess collapse, usually 24–72 hours. Irrigation may be required. Less optimally, single or, if required, multiple discrete aspirations can be performed instead of leaving a catheter in place. Potential contraindications to these techniques include inaccessible lesions and ascites. Complications include peritonitis, formation of additional abscess collections, fistula formation, hepatic laceration, and hemorrhage. Patients in whom percutaneous drainage is not feasible, is not successful, or in whom an additional source of intra-abdominal infection (or biliary obstruction) exists, may require open drainage procedures.


Non-operative management may also play a role, primarily in patients with multiple abscesses. Success in this instance is more likely when abscesses are small. Duration of antibiotic therapy is variable. Treatment periods of three to six weeks are generally accepted. Prognosis is as denoted above but is worse in patients with multiple abscesses.



Cholangitis

Bacterial cholangitis, or infection of the biliary system, is a relatively uncommon event in pediatrics. At-risk patients are those with abnormalities of the biliary tract, particularly following hepatic portoenterostomy after a diagnosis of biliary atresia. Risk of cholangitis after the Kasai procedure is approximately 40–50% [13], with highest incidence occurring in the first three months after surgery. Late-onset cases have also been reported. Other conditions that may predispose to cholangitis include choledocholithiasis, choledochal cyst, and Caroli disease. Rarely, cholangitis in the absence of other risk factors may be noted.


The etiology of cholangitis is multifactorial. The normal biliary tract is sterile; the sphincter of Oddi aids in the prevention of bacterial reflux into the biliary tree from the duodenum. Destruction of this sphincter mechanism, as occurs in the Kasai procedure, may be associated with ascending bacterial colonization from the bowel. Indeed, patients in whom adequate bile drainage is attained after the Kasai procedure have a higher incidence of cholangitis than do those in whom surgery was unsuccessful. This illustrates the importance of direct contact between the biliary system and bowel flora in the pathogenesis of cholangitis. Biliary infection may also be produced via portal bacteremia. Conversely, the presence of bacteria in the bile is probably not sufficient to produce clinically significant cholangitis. It is likely that a combination of biliary obstruction and infected bile is required. In this regard, biliary parasites may play an important role.


Classically, the combination of right upper quadrant abdominal pain, fever, and jaundice (the Charcot triad) has been associated with the majority of adults with cholangitis.


Bowel sounds are generally present. Hypotension may be a presenting feature in under half of adults. Presenting clinical features in a series of children after the Kasai procedure included fever (100%), acholic stools or increase in serum bilirubin (68%), shock, and decrease in bile flow (43%) [13]. Associated laboratory findings include leukocytosis or leukopenia, elevated ESR, and, as noted, increased serum bilirubin. Other features often noted in series of adult patients include elevation of serum alkaline phosphatase and aminotransferases. Further diagnostic evaluation of the patient with suspected cholangitis should include bacteriologic cultures of the blood and urine. Blood cultures may provide the etiologic organism in approximately 50% of patients [13]. Initial imaging studies should include either ultrasonography or CT scanning to evaluate for (1) abscess formation associated with cholangitis; (2) presence of calculi; (3) presence of ductal dilation; or (4) other obstructing lesions including choledochal cyst or periportal mass. Magnetic resonance cholangiopancreatography (MRCP) may also be useful in selected patients [14]. Patients in whom culture results are negative, and in whom the clinical picture warrants it, should undergo a percutaneous hepatic biopsy, for both culture and histologic examination. Performed in the presence of normal coagulation parameters, this procedure has been shown to be relatively safe, and, at least in adult series, may be safely performed in the presence of ductal dilation. Hepatic culture was positive in 32 of 69 children with presumed cholangitis [13]. E. coli was the most frequently isolated pathogen (50% of first and second cholangitis episodes) in this and other studies. Other commonly isolated organisms include Klebsiella sp., enterococci, Bacteroides sp., Enterobacter sp., and Pseudomonas sp. Anaerobic organisms may also be isolated; mixed cultures are not uncommon. In approximately 30% of episodes, no bacterial agent is identified. Hepatic histologic changes may be useful in these cases. Pathologic alterations include infiltration of the portal triads, bile ductules, and ductule lumens with neutrophils. Portal edema may occur, as may changes consistent with biliary obstruction (Figure 39.3) [15].





Figure 39.3 Cholangitis following hepatic portoenterostomy. The lumen of the bile duct is filled with acute inflammatory cells and necrotic debris. Neutrophils extend into the bile duct epithelium and surrounding portal tract stroma. The epithelium lining the bile duct is reactive and focally attenuated.


Therapy of acute cholangitis includes careful attention to vital signs and perfusion status, providing adequate fluid resuscitation and pressure support if needed. The patient is made nil by mouth; nasogastric suction may be required in the presence of ileus. Toxic patients with evidence of biliary obstruction may require emergency intervention, endoscopic, percutaneous or, less commonly, operative. In most other patients, intervention should be withheld until after several days of antibiotic therapy and reduction of fever. Antibiotic therapy is initially given by the parenteral route. Choice of antibiotics is governed by sensitivities of common organisms, and the achievable serum and biliary antibiotic levels. Potential choices include intravenous ampicillin and sulbactam, third-generation cephalosporins (e.g., cefotaxime), or ampicillin in combination with an aminoglycoside. Alternatively, a broad-spectrum penicillin derivative with good biliary penetration (e.g., mezlocillin) may be utilized. The newer penicillin derivatives have the advantage of covering Enterococcus (was Streptococcus) faecalis as well as a variety of anaerobic organisms. Mezlocillin used alone has been prospectively compared with an ampicillin/gentamicin regimen in the treatment of cholangitis in adults and found to have a higher rate of cure in addition to a lower incidence of toxicity [16]. Ciprofloxacin has gained acceptance in the therapy of cholangitis in adults but its use in young children continues to be debated. Trimethoprim–sulfamethoxazole has also been utilized. Particularly ill patients may require addition of specific anaerobic coverage, as well as the use of other antibiotic combinations including piperacillin/tazobactam, ticarcillin/clavulanate, imipenem, or meropenem [17]. Duration of treatment is generally 21 days for severe disease.


Biliary decompression may be required in those patients with biliary obstruction. Initial data regarding site of obstruction may be garnered through use of spiral CT and/or MRCP [14]. Subsequently, ERCP and placement of nasobiliary drainage tubes after papillotomy and stone removal (if necessary) is performed. These procedures have now been safely performed in significant numbers of children [18]. Subsequent cholangiography may delineate the site of obstruction, allowing definitive therapy to be undertaken endoscopically in select cases. Percutaneous cholangiography and decompression have also been advocated. Finally, surgical intervention may be required in some patients.


The prognosis of cholangitis in children has not been clearly delineated, but in one study of cholangitis after the Kasai procedure, the mortality rate was approximately 1% [13]. Mortality in adult series is considerably higher, presumably because of the higher incidence of malignant lesions and debilitated patients in these groups. Repeated episodes of cholangitis can result in the cessation or diminution of bile flow in those patients who have undergone successful Kasai procedures. Therefore, aggressive diagnostic and therapeutic efforts seem justified in this population.



Perihepatitis


First noted by Stajano in 1919, Fitz-Hugh (1934) [19] and Curtis (1930) [20] independently described the syndrome of perihepatitis associated with salpingitis that now bears their names. Generally noted in young women, symptoms include acute-onset, severe right upper quadrant pain, occasionally with radiation to the shoulder and back. Pain is intensified by the intake of breath or palpation of the abdomen. A friction rub may be present over the anterior liver surface. Fever may be present. The patient often has both a history of previous pelvic inflammatory disease and physical findings suggestive of the same. Laboratory findings are non-specific but often include an elevated ESR. Serum aminotransferase levels are normal or minimally elevated. Abdominal CT may reveal hyperemia of the anterior liver surface. Laparoscopic (laparotomy) findings early in the course of perihepatitis include “violin string” adhesions between the hepatic capsule and the adjacent abdominal wall and diaphragm. Later findings consist of hemorrhagic spots and white fibrous plaques on the liver surface. The hepatic parenchyma does not appear involved. Diagnosis in the proper clinical situation is made via isolation of the causative microorganisms, Neisseria gonorrhoeae and/or Chlamydia trachomatis from the cervix, urethra or rectum, or, more commonly, via polymerase chain reaction (PCR) of an appropriately collected urine. The pathophysiology of perihepatitis associated with salpingitis remains uncertain. Postulated mechanisms include ascending infection from the genital tract to the perihepatic region, as well as spread via the bloodstream. Treatment is through eradication of the underlying infection with an appropriate antibiotic regimen.


The liver may also be involved in patients with gonococcal bacteremia; approximately 50% may have abnormalities of serum aminotransferase levels [21].



Specific Bacterial Infections



Cat Scratch Disease

Cat scratch disease, caused by pleomorphic gram-negative bacteria identified as Bartonella henselae, typically consists of regional lymphadenitis following inoculation of the responsible agent, usually by a cat. Clinical manifestations may also include encephalitis, pneumonitis, arthritis, osteomyelitis, and neuroretinitis, among many others [22]. While hepatosplenomegaly and anicteric hepatitis had previously been reported in association with cat scratch disease, the association with hepatic and splenic abscesses was first noted in 1985 [23]. Affected patients often present with systemic symptoms including fever, chills, myalgia, malaise, and abdominal pain. Clinically evident adenopathy is generally but not universally present. Elevated ESR is frequently observed, while serum aminotransferases, bilirubin, and alkaline phosphatase levels are typically normal. Abdominal imaging studies, usually performed as part of an evaluation for fever of unknown origin, reveal multiple, small, hypodense lesions in the parenchyma of the liver and spleen (Figure 39.4). B. henselae antibody titers are characteristically elevated. At surgery, firm nodules are noted. Biopsy often reveals necrotizing granulomatous hepatitis [23]. Organisms may be noted within the lesions (Figure 39.5). Direct confirmation of identity may be made through the demonstration of B. henselae DNA in the hepatic tissue via PCR. Differential diagnosis includes other causes of hepatic granulomas, including infection with a variety of bacterial, fungal, parasitic, and viral agents. In addition, neoplasms, hypersensitivity reactions, and sarcoidosis must be considered. In the absence of widely available culture techniques for the cat scratch bacilli, precise diagnosis in the proper clinical situation (e.g., lymphadenopathy, history of cat contact and/or scratch, and identification of inoculation site) necessitates elimination of other causes of granulomatous hepatitis.





Figure 39.4 Cat scratch disease. CT of the liver and spleen shows multiple areas of low attenuation throughout the hepatic and splenic parenchyma.





Figure 39.5 Cat-scratch disease. (A) Portal region showing non-specific chronic lymphocytic inflammation extending across the limiting plate of an adjacent hepatic lobule. (B) Several extracellular bacilli located within the collagenous matrix (Warthin–Starry silver stain).


Therapy in the immunocompetent host remains problematic but some authorities recommend parenteral antibiotic treatment, often gentamicin [24], for up to three weeks. Potentially effective oral therapy includes trimethoprim–sulfamethoxazole, rifampin, azithromycin dihydrate, and ciprofloxacin [24]. Corticosteroids have also been employed when there is persistent fever [22]. Recovery appears to be complete.



Typhoid Hepatitis

Typhoid fever, most often caused by Salmonella typhi and Salmonella paratyphi (ser.) is a syndrome characterized by fever, headache, and abdominal pain. A relative bradycardia may be present. Subsequent findings may include pneumonia and encephalopathy. Intestinal perforation or bleeding may occur. Approximately 27% of patients have hepatomegaly [25], and 5–10% of patients will have clinical jaundice. Serum aminotransferases and alkaline phosphatase are mildly abnormal in 50% of cases. In one series, symptoms of hepatitis were present in 5% of patients [25]. A recent series demonstrated abnormal liver chemistries in 36% of patients with Salmonella enteritidis enterocolitis [26]. Hepatic biopsy findings are relatively non-specific and include the presence of typhoid nodules (focal areas of hepatocyte necrosis surrounded by a mononuclear cell infiltrate), sinusoidal dilation, and mononuclear cell inflammation of portal tracts. Less frequently noted were ballooning degeneration of hepatocytes, steatosis, and hepatic granulomata [27]. Typically, findings were noted in combination and could be found in biopsies from patients without hepatomegaly. Diagnosis is established via culture and/or serology. Hepatic abnormalities typically resolve with treatment of the underlying infection.



Brucellosis

Brucellosis, in humans generally attributable to Brucella melitensis, B. abortus, or B. suis, is an often prolonged illness characterized in children by fever, weight loss, malaise, arthralgia, back pain, and headache. Complications may include abscess formation, meningoencephalitis, pneumonitis, osteomyelitis, nephritis, and endocarditis. Infection is typically acquired via contact with infected animals or ingestion of contaminated milk products.


Hepatic involvement in brucellosis is relatively common. Approximately 25% of affected children have hepatosplenomegaly on physical examination [28] and 84% have abnormal hepatic enzyme studies [29]. Clinical jaundice is relatively infrequent, as is cholecystitis, either calculous or acalculous [30]. Common laboratory abnormalities in children include lymphocytosis and elevation of the ESR. Liver biopsy findings include portal inflammation and focal hepatocyte necrosis in 90% of patients [31], while non-caseating granuloma formation may be noted in up to 70% of patients, primarily within the first 100 days of illness. Diagnosis is made through history of possible exposure, culture and PCR of infected tissue, as well as by specific serology. Treatment is with tetracycline or doxycycline in conjunction with rifampin. Trimethoprim–sulfamethoxazole may be utilized in children under nine years of age. In rare cases of hepatic abscess secondary to Brucella infection, drainage or surgery may be required in addition to medical therapy.



Tularemia

Caused by infection with Francisella tularensis, tularemia may occur in typhoidal or ulceroglandular forms. Infection is typically via exposure to infected mammalian vectors (e.g., rabbits, squirrels, dogs, cats) or through tick bites, although other more tangential methods of spread have been reported. Hepatic involvement appears to be relatively infrequent; however, one series reported abnormal liver tests in 58% [32]. Hepatomegaly, clinical hepatitis, and hepatic abscess formation have all been reported. Pathologic findings in tularemic hepatitis include focal coagulative necrosis with chronic inflammatory infiltrate. Diagnosis is via examination of serum F. tularensis titers and culture. Treatment is with streptomycin or aminoglycoside antibiotics. Ciprofloxacin and doxycycline may be indicated for mild disease [24].



Yersinia Enterocolitica

Yersinia enterocolitica has been implicated in the development of hepatic abscesses in the setting of hemochromatosis in adults [33].



Toxic Shock Syndrome

Toxic shock syndrome is described as a complication of tampon use but is a consequence of bacterial infection generally attributable to staphylococcal and streptococcal species. In the former, staphylococcal toxin TSST-1 acts as a superantigen, causing a ctytokine storm via T-cell activation.


Diagnostic criteria include fever, diffuse macular rash with desquamation (primarily of palms and soles one to two weeks after disease onset), hypotension, involvement of three or more organ systems, including CNS, liver, kidney, muscles, gastrointestinal tract, and mucous membranes, plus negative work-up for other potential causes. Hepatic involvement in toxic shock syndrome has been described by several investigators. Cholestasis, as delineated by elevated serum bile acid and bilirubin levels, has been noted in conjunction with elevated serum aminotransferases. Pathologic changes consistent with an acute cholangitis have been described [34]. Other observed alterations included portal inflammation and steatosis. Minimal intrahepatic cholestasis was noted. Hepatic abnormalities resolve with adequate anti-infective therapy, generally consisting of a beta-lactamase-resistant antistaphylococcal agent in conjunction with clindamycin, which inhibits bacterial protein synthesis [24].



Streptococcal Infection

Infections with Group A β-hemolytic streptococci have long been associated with hepatic dysfunction. Jaundice has been reported as both an early and late complication of scarlet fever; the late-onset component may have reflected use of serum therapy in the early 1900s [35]. Early-onset jaundice was noted in association with hepatic tenderness and hepatomegaly. Pathologic findings include focal areas of hepatocyte necrosis, as well as portal inflammatory infiltrates consisting of polymorphonuclear leukocytes and lymphocytes. Streptococci may be noted in biopsy specimens [35, 36]. The etiology of observed alterations is unclear but may involve direct infection vs. toxin effect. Streptococcal infection has also been associated with fulminant hepatic failure.


Pneumococcal infections (Streptococcus pneumoniae), including those manifested as pneumonia, are also associated with a high incidence of hepatic enzyme abnormalities and, less frequently, jaundice [37]. Differential diagnosis of pneumonia associated with cholestasis must also include that caused by Legionella sp.



Listeriosis

Listeria monocytogenes is a gram-positive bacillus that may be acquired transplacentally, perinatally, or via genital contact. Nosocomial and food-borne outbreaks have also been reported. Neonates, those with pre-existing hepatic disease (including hepatic transplantation), and immunosuppressed individuals are most at risk. The disorder is characterized by the formation of granulomas. In neonates, the liver is often diffusely involved. Hepatic involvement is noted less often in older individuals. Other clinical manifestations may include, depending upon age, respiratory distress, cardiac dysfunction, meningitis, endocarditis, and osteomyelitis. Diagnosis is made through the use of cultures. Treatment is generally undertaken with ampicillin in combination with gentamycin or other aminoglycosides [24].



Mycobacterial Infections


Tuberculosis

Involvement of the liver in tuberculosis is well known. In congenital tuberculosis, the liver is often the primary site of infection, perhaps because of blood flow through the ductus venosus. In older patients, the liver is also frequently affected. Up to 75% of patients with extrapulmonary tuberculosis [38], as well as most patients with miliary tuberculosis, have hepatic involvement, as do smaller proportions of those with pulmonary involvement. Hepatic manifestations are heterogeneous; most common are small hepatic granulomas found in portal areas. Early granulomas are composed of lymphocytes and epithelioid cells; subsequently giant cell formation and necrosis may predominate. Lesions may reach 1–2 mm in size in miliary tuberculosis (Figure 39.6) [39]. Larger 1–2 cm tuberculomata may be seen, as may tuberculous hepatic abscesses, either in conjunction with an extrahepatic foci of infection or as a primary lesion. Biliary obstruction may occur as the result of perihilar adenopathy. Presenting symptoms typically depend upon the location of associated disease; most hepatic disease attributed to tuberculosis is asymptomatic. Congenital tuberculosis may present in the first one to two weeks of life with failure to thrive; hepatosplenomegaly and jaundice may be later manifestations. In older patients, weight loss, fever, and anorexia predominate; abdominal pain is sometimes present. Hepatomegaly is common; splenomegaly is less frequently appreciated. Jaundice may occur, as may ascites. Alkaline phosphatase levels are abnormal in approximately 75% of patients and aminotransferase levels in 35%. Plain film of the abdomen may reveal large, confluent, hepatic calcifications as well as calcifications along the course of the common bile duct. Liver CT may reveal abscess formation; ring enhancement may be present. It may also reveal the diffuse, small, low-density lesions typical of miliary tuberculosis. Duct dilation may be noted with CT or ultrasonography. Delineation of the site of ductal obstruction may require endoscopic retrograde cholangiography and/or percutaneous transhepatic cholangiography. Laparoscopy may be a highly specific means of diagnosing hepatic tuberculomata; visible lesions were found in 49 of 53 patients examined [40]. Diagnosis generally requires biopsy; both histology (with appropriate stains for acid-fast bacteria) and culture should be performed. Culture of other sites, including gastric aspirate, sputum, and bone marrow, may be appropriate as well as measurement of ex vivo interferon-gamma production from T lymphocytes in response to antigens specific to M tuberculosis complex.





Figure 39.6 Miliary tuberculosis. Numerous oval epithelioid granulomas are scattered throughout the liver.


Treatment is that of active tuberculosis; for susceptible strains, two months of isoniazid, rifampin, and pyrazinamide daily, followed by four months of isoniazid and rifampin. Regimens include daily observed therapy during the intensive phase of treatment [41]. Early, aggressive therapy is of particular importance in congenital tuberculosis [42]. Abscesses may require percutaneous catheter placement and drainage; surgery is occasionally required. The prognosis of hepatic tuberculosis in children is unclear. The worst prognosis may be in neonatally acquired infection.



Mycobacterium Avium Complex

Mycobacterium avium complex has also been associated with liver disease, generally in the setting of profound immunodeficiency associated with advanced HIV infection. Liver disease generally occurs in the context of systemic disease. Elevated serum aminotransferases and alkaline phosphatase are frequently noted. Granulomas containing prominent foamy macrophages may be noted on liver biopsy: acid-fast bacilli may be seen in some cases (Figure 39.7) [43]. Diagnosis of disseminated infection generally is made by culture of blood, sputum, or feces. Treatment is through the use of a combination of at least two drugs with antimycobacterial activity; ethambutol and clarithromycin are most often used. Prophylaxis with azithromycin or clarithromycin is recommended for HIV-infected patients with profound immunosuppression [44].





Figure 39.7 Mycobacterium avium complex. (A) Non-necrotizing epithelioid granuloma are formed of large foamy histiocytes. (B) Acid-fast bacillus stain demonstrates bacilli engulfed by histiocytes.



Actinomycosis

Actinomycosis is caused by Actinomyces israelli, a ubiquitous organism found worldwide. Part of normal human oral flora, A. israelli may also be responsible for infections of the cervicofacial, abdominal, and thoracic regions. Hepatic infection typically occurs via direct extension or portal vein seeding from other intra-abdominal foci of infection. Hepatic infection may be primary in 15% of cases [45]. Early hepatic infection may present non-specifically as hepatitis. Subsequent infection results in hepatic abscess formation. Advanced infection may also mimic hepatic neoplasia. Sinus formation is common and may discourage attempts at percutaneous aspiration in suspected cases. Diagnosis is made by positive culture and demonstration of “sulfur” granules, diagnostic of actinomycosis. Therapy is with high-dose intravenous penicillin; subsequent oral therapy may include amoxicillin/penicillin or a tetracycline. Treatment for up to one year may be necessary [24]. Surgical resection of large lesions may be required.



Ehrlichioses

The ehrlichioses are a group of tick-borne diseases caused by bacteria of the genus Ehrlichia. These bacteria infect either human monocytes (Ehrlichia chaffeensis; transmitted by Lone Star ticks) or human granulocytes (human granulocyte ehrlichiosis agent; transmitted by Ixodes scapularis and I. pacificus). Symptoms include fever, headache, myalgia, and malaise. Complications include prolonged fever, shock, adult respiratory distress syndrome, mental status changes, pneumonitis, and rhabdomyolysis, among others. Approximately 70–90% of affected patients demonstrate abnormal serum aminotransferases, peaking on day six to seven of illness at approximately ten times normal values, and then decreasing slowly as the illness resolves. Immunosuppressed patients may have smaller increases in aminotransferases [46]. Liver pathology has been studied in a limited number of patients. Cholestasis, with neutrophilic infiltration of the bile duct epithelium suggesting bile duct obstruction, has been noted [47]. Sinusoidal monocytic infiltration has been a more common finding. Others note focal hepatic necrosis and/or ring granuloma formation. Diagnosis is made through serology and PCR. Treatment is generally undertaken with doxycycline [24]. Hepatic abnormalities resolve completely after therapy.



Syphilis

The liver is a common site of involvement in both congenital and secondary syphilis. Indeed, transfer of treponemes across the placenta into the fetal circulation presumably accounts for the widespread organ involvement noted in congenital syphilis. Symptomatic infants are often small for gestational age, with evidence of lymphadenopathy, hemolytic anemia, and thrombocytopenia. Bony abnormalities may occur in 80–90% of affected infants, while rash occurs in 40–60%. Other associated findings include neurologic disease, dental and ocular abnormalities, and nephrosis. Hepatic involvement is frequent, with hepatomegaly estimated to occur in 50–90% of symptomatic infants. Rarely, hepatic failure may occur [48]. Conjugated hyperbilirubinemia may also occur. Diagnosis is made through use of serology. Evaluation of the infant with findings suggestive of congenital syphilis should include serum VDRL (Venereal Disease Research Laboratory test), radiography of the long bones, and examination of cerebrospinal fluid. Hepatic biopsy is generally not required for diagnosis. Wright and Berry reviewed liver sections from 59 children who died of congenital syphilis in the pre-antibiotic period; 50 of the 59 sections were “histologically normal,” but 41 were “heavily infiltrated with treponemes, so much that it appeared that there were more treponemes than liver” [49]. Conversely, specimens from children treated with penicillin often show histologic changes consisting of extramedullary hematopoiesis, parenchymal and portal inflammation, and occasional focal scarring, leading to the hypothesis that penicillin therapy may exacerbate syphilitic hepatitis. Nonetheless, penicillin remains the cornerstone of therapy for affected infants. Although syphilitic hepatitis may persist for weeks or months following treatment, the process generally resolves without sequelae.


Hepatic involvement is also a well-recognized consequence of secondary and tertiary syphilis. Approximately 50% of patients with secondary syphilis have hepatic enzyme abnormalities, while jaundice is significantly less common, occurring in 1–12% of affected patients. Serum alkaline phosphatase values are often disproportionately elevated. Biopsy findings are variable but may include areas of focal necrosis encircled by lymphocytes, neutrophils, and eosinophils. Granulomatous changes may be present, as may pericholangitis. In tertiary syphilis, gumma formation is noted. Resolution is typically complete following adequate treatment of the underlying infection.



Borreliosis


Lyme Disease

Lyme disease is caused by Borrelia burgdorferi, a tick-borne spirochete. Acute signs and symptoms include erythema chronicum migrans, fever, malaise, headache, stiff neck, arthralgias, myalgias, and lymphadenopathy. Arthritis may be chronic. Hepatic involvement in humans has been described; 19–37% may have abnormal liver tests [50]. Symptoms consistent with hepatic dysfunction may be elicited and include nausea, vomiting, anorexia, and weight loss. Hepatomegaly and right upper quadrant pain may be noted. Liver biopsy in one patient revealed infiltration of sinusoids by neutrophils and mononuclear cells [51]. Microvesicular fat, Kupffer cell hyperplasia, ballooning hepatocytes, and increased hepatocyte mitotic activity were also noted. B. burgdorferi organisms were present in the biopsy specimen [51].


Diagnosis of Lyme disease requires a high index of suspicion on the part of the investigating physician. History of travel to affected areas, or of clinical signs/symptoms consistent with infection, must be elicited and appropriate serologic studies performed (enzyme-linked immunosorbent assay (ELISA) or indirect fluorescent antibody, followed by Western blotting if positive). Assessment with PCR, if available, may also be of use. Treatment of early disease is with doxycycline [24]; cefuroxime or amoxicillin may be used in children under nine years of age. Parenteral therapy with ceftriaxone may be required in those patients with severe carditis, persistent arthritis, or meningitis. Chronic hepatitis has not been described with B. burgdorferi infection.



Borrelia Recurrentis

Patients with Borrelia recurrentis infection are also known to have hepatic involvement. In a series of patients with louse-borne disease, 62% were noted to have hepatic tenderness [52]. Patients may have mild elevation of serum aminotransferases; jaundice may also occur. Diagnosis is via examination of blood smears for Borrelia. Treatment with doxycycline, erythromycin, and penicillin may be effective, particularly if the diagnosis is made early in the disease course.



Leptospirosis

Leptospirosis is caused by one of several serotypes of Leptospira interrogans, a coiled, motile spirochete whose primary hosts include a variety of domestic and wild animals. At-risk individuals have traditionally included those exposed to cattle, dogs, horses, and rats. Exposure to blood, other body fluids, or fluids contaminated by urine from affected animals may result in disease transmission to humans. Disease in children has been attributed to canine exposure. After an incubation period of four to 20 days, one of two general disease patterns may occur. Approximately 90–95% of patients in adult series will remain anicteric and undergo an initial phase of disease lasting four to nine days, marked by the presence of spirochetes in the peripheral circulation and characterized by fever, anorexia, abdominal pain, conjunctival erythema, lymphadenopathy, rash, and muscle tenderness. Headache and, less often, nuchal rigidity may occur. Approximately 50% of patients undergo a second period of fever, often marked by meningeal involvement, hepatitis, and, occasionally, endocarditis and myocarditis. In 5–10% of patients, there will be a more severe course, marked by significant jaundice, renal failure, hemorrhage, and vascular collapse, with death occurring in up to 40%. Children with leptospirosis suffer many of the signs and symptoms noted above. Hepatomegaly was seen in five of nine hospitalized children with leptospirosis; acalculous cholecystitis was also noted in five, serum bilirubin >1.2 mg/dL in seven, and elevated serum aminotransferase in six [53]. More recent series have confirmed these differences in presentation between children and adults. Also in contrast to data from adult series, severe disease in children is not limited to the icterohemmorhagiae serogroup of L. interrogans. Other abnormal laboratory findings may include elevated serum creatinine phosphokinase, leukocytosis, thrombocytopenia, and proteinuria. Serum prothrombin time may be elevated but generally normalizes in response to vitamin K administration.


The pathophysiology of leptospirosis-associated hepatic disease remains uncertain. Hepatic biopsy findings include edema, disorganization of liver cell plates, and multinucleated cells, reflecting hepatocyte proliferation (Figure 39.8). Erythro- phagocytosis may be seen [54]. In approximately 10% of patients, small foci of hepatocellular necrosis may be present. Histologic alterations do not correlate with degree of jaundice. Diagnosis of leptospirosis may be made via culture of blood or cerebrospinal fluid during early stages of illness, and from urine subsequently. Serology (ELISA, microscopic agglutination test) and PCR may also be of use, because culture of this organism is often difficult. Although not diagnostic, darkfield examination of the urine may provide useful information.





Figure 39.8 Leptospirosis. Numerous spirochetes are present. Detail of the spirochete coiling is somewhat obscured by the silver deposits in this silver impregnation-based stain (Warthin–Starry).


Treatment of affected individuals with parenteral penicillin appears most efficacious if initiated within the first few days of illness [24]; ceftriaxone, cefotaxime, and doxycycline are also of use. Doxycycline may serve as effective prophylaxis in high-risk individuals.



Rickettsial Disease

Rocky Mountain spotted fever, the clinical syndrome associated with Rickettsia rickettsii infection, is characterized by fever; petechial rash beginning peripherally, spreading to the trunk, and often involving the palms and soles; and headache. Ticks serve as vectors for disease transmission. Hepatic involvement may occur; clinical manifestations include hepatomegaly and, rarely, jaundice. Pathologic changes noted at autopsy have consisted of portal triaditis, portal vasculitis, and erythrophagocytosis. Rickettsial organisms may be found in portal blood vessels and/or sinusoidal lining cells [55]. Diagnosis is via serology and high index of clinical suspicion. Treatment is with doxycycline.



Q Fever

Q fever is caused by Coxiella burnetti, a proteobacteria, and is characterized by fever, headache, malaise, myalgia, and pneumonitis, although asymptomatic infection predominates in humans. Transmission occurs largely via inhalation of the Coxiella organism; this mode of transmission differs from rickettsiae, with which Q fever has been historically associated [56]. Animal hosts include cattle, sheep, goats, and rodents. Transmission may also occur through ingestion of contaminated milk.


Symptomatic infection in humans lasts 9 to 16 days, although acute infection may last up to three months. Chronic infection may occur, primarily in the form of Q fever endocarditis and osteomyelitis. Hepatic involvement is frequent in acute Q fever. Specifically, 70–85% of patients are noted to have abnormal liver tests, and 11–65% are noted to have symptoms referable to hepatic involvement [57]. Hepatomegaly (16%) and hepatic tenderness may be present [56]. In one center, 42% of patients with Q fever presented with hepatitis in the absence of pulmonary symptoms [57]; 5% of patients present with jaundice. Although uncommon, hepatic failure secondary to Q fever has been documented in children. Pathologic findings in the liver of patients with acute Q fever classically include fibrin ring granulomas, consisting of a central clear space surrounded by histiocytes and a fibrin ring (Figure 39.9). Early lesions may contain neutrophils, while giant cells are noted in later lesions [58]. Non-specific changes include steatosis, mononuclear infiltration of portal areas, and Kupffer cell hyperplasia. Fibrosis may rarely occur; hepatitis may rarely become chronic. Diagnosis is via detection of antibodies to phase II antigens of C. burnetti and/or PCR. Treatment is usually problematic because of the self-limited nature of most infections; however, doxycycline is efficacious; co-trimoxazole is recommended for children younger than eight years of age.


Feb 26, 2021 | Posted by in GASTROENTEROLOGY | Comments Off on Chapter 39 – Bacterial, Parasitic, and Fungal Infections of the Liver in Children
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