Clinical Aspects of Liver Diseases 23 Acute concomitant viral hepatitis

Clinical Aspects of Liver Diseases

23 Acute concomitant viral hepatitis

Page:

1 Secondary hepatotropic viruses 464

1.1 Herpesviruses 464

1.1.1 Infectious mononucleosis 464

1.1.2 Herpes simplex hepatitis 465

1.1.3 Herpesvirus hepatitis 466

1.1.4 Varicella-zoster hepatitis 466

1.1.5 Cytomegalovirus 466

1.2 Togaviruses 467

1.2.1 Rubella hepatitis 467

1.2.2 Spring-summer encephalitis hepatitis 467

1.3 Picornaviruses 467

1.3.1 Coxsackie hepatitis 467

1.3.2 ECHO virus hepatitis 467

1.4 Paramyxoviruses 467

1.4.1 Measles hepatitis 467

1.4.2 Parotitis hepatitis 467

1.4.3 Giant-cell hepatitis 467

1.5 Adenovirus hepatitis 467

1.6 Human parvovirus B 19 467

1.7 HIV hepatitis 467

2 Exotic hepatotropic viruses 468

2.1 Yellow fever 468

2.2 Dengue fever 469

2.3 Marburg virus disease 469

2.4 Lassa haemorrhagic fever 469

2.5 Ebola haemorrhagic fever 469

2.6 Rift Valley fever 470

앫 References (1⫺113) 470

(Figures 23.1 ⫺23.5; tables 23.1⫺23.2)

A multitude of viruses can affect the liver as a large, filtrating and reacting organ, and subsequently cause concomitant viral hepatitis in the course of an exist- ing systemic viral infection. Laboratory and histolog- ical findings in this case are determined by the type of pathogen, including its particular hepatotropic character, and by the immune status or reactivity of the affected organism. Concomitant viral hepatitis does not generally cause symptoms, which is why it is often recognized purely by chance due to slight to moderate elevations in transaminases; minor in- creases in bilirubin or cholestasis-indicating enzymes are rarely detectable. Nevertheless, rather severe courses with vast hepatocellular necrosis can occur in patients with a weakened immune response. • In infancy, concomitant viral hepatitis is frequently accompanied by a predominant cholestasis syn- drome. On the one hand, an infant liver can be dam- aged by virus infections of a severe and even fatal course, yet on the other hand, it displays an astonish- ing capacity for regeneration and is indeed capable of restoring destroyed liver structures.

1 Secondary hepatotropic viruses

The most important virus species with regard to their ability to cause concomitant inflammatory reactions of the liver are (1.) herpesviruses, (2.) rubella viruses, (3.) Coxsackie viruses, and (4.) paramyxoviruses. (s. tab. 23.1)

1. Herpesviruses

⫺ Epstein-Barr virus D E

⫺ Herpes simplex virus 1, 2 D E

⫺ Human herpesvirus 6, 7, 8 D E

⫺ Varicella-zoster virus (D)

⫺ Cytomegalovirus D E

2. Togaviruses

⫺ Rubella virus D E

⫺ Spring-summer encephalitis virus D E 3. Picornaviruses

⫺ Coxsackie virus D E

⫺ ECHO virus D E

4. Paramyxoviruses

⫺ Measles virus E

⫺ Parotitis virus (D)

⫺ Giant-cell hepatitis virus D E

5. Adenoviruses (S D E)

6. Human parvovirus B19

7. HIV laboratory test⫹

Tab. 23.1: Secondary hepatotropic viruses which can cause viral hepatitis. • In Germany,obligation for notification is given in cases of suspicion (S), disease (D) or exitus (E). This can, however, vary from country to country. If in doubt, contact the Public Health Department!

1.1 Herpesviruses

Out of a group of approximately 40 herpesviruses (con- taining DNA, 100 nm in length), the following are clas- sified as secondary hepatotropic: (1.) Epstein-Barr virus (types A, B), (2.) herpes simplex virus, (3.) herpesvirus-6, (4.) varicella-zoster virus, and (5.) cytomegalovirus.

1.1.1 Infectious mononucleosis

“Pfeiffer’s glandular fever” (E. Pfeiffer, 1889) or “infectious mononucleosis” (T. P. Sprungt et al., 1920) is caused by the human herpesvirus 4 (⫽ EB virus 4), which was discovered by M. A. Epstein,B. G. AchongandY. M. Barrin 1964.

Infectious mononucleosis is a generalized reticuloendo- thelial infection, mainly found in adolescents and young adults. The total endemic infection rate in the more advanced age groups is 80 ⫺100%. • This condition is transmitted by close physical contact (“kissing dis- ease”), sexual contact and blood transfusion. The incu- bation period of the orally transmitted virus is 8 ⫺21 days (up to 7 weeks). This is followed by a prodromal stage with headaches, tiredness and atypical fever. The clinical picture is defined by (chiefly cervical) swollen lymph nodes (95 ⫺100%), tonsillitis (>80%), splenomeg- aly (> 50%), exanthema, mucosal petechiae in the oral cavity (30 ⫺50%) and leucocytosis with very large num- bers of lymphomonocytoid cells. These “atypical lym- phocytes”

are activated T cells. Gall- bladder wall thickening is found by sonography.

In about 50% of cases, hepatitis mononucleosa with hepatomegaly (10 ⫺25%) develops, displaying an in- crease in transaminases of 10 ⫺20 times the normal value.

Jaundice is witnessed in 5 ⫺10% of cases, usually due to autoimmune-based haemolysis.

There is a distinct elevation of LDH and alkaline phos- phatase.

Hence, the following enzyme constellation can be evaluated as the biochemical triad of hepatitis mononucleosa:

LDH 앖앖앖 (90ⴚ95%)

AP 앖앖 (75ⴚ90%)

GPT, GOT 앖 (60ⴚ90%)

The Paul-Bunnel test

,

is posi-

tive from the 4

to 10

day in about 75% of cases. Sero-

logical proof of acute infection can be successfully

obtained by way of anti-EB virus IgM. The virus DNA

is revealed by PCR. • Hepatic lesions are already found

as from the 5

day and are most distinct between the

10

and 30

day of the disease. Portal/periportal and

sinusoidal infiltrations of partially beaded lympho-

monocytoid cells frequently appear in the form of small

Acute concomitant viral hepatitis

foci. Proliferations of Kupffer cells and bile capillaries as well as isolated focal hepatocellular necroses and granulomas are present.

(s. fig. 23.1)

Fig. 23.1: Agglomeration of activated Kupffer cells (partially beaded), especially in the sinusoidal vessels, with single-cell necrosis. Clinical diagnosis: hepatitis mononucleosa (HE)

䉴 We observed a severe haemolytic course in a 23-year- old man, which took 4 months to subside: total bilirubin up to 34.8 mg/dl, haemoglobin decline to 7.7 g%, LDH up to 1,720 U/l, reticulocytosis 54‰, GPT 110 U/l, GOT 60 U/l, AP 308 U/l, γ-GT 148 U/l, increased erythropoie- sis in bone marrow ⫹⫹, direct Coombs’ test ⫹⫹, cold agglutinin ⫹⫹, and incomplete cold haemolysin ⫹⫹. (s.

fig. 23.1)

Some of the more serious extrahepatic complications are splenic rupture, thrombocytopenia, myocarditis or peri- carditis, meningitis, pneumonia, nephritis and haemo- lytic anaemia; ascites was also reported in the course of severe hepatitis.

It should be noted that EBV can sometimes trigger autoimmune hepatitis.

• The prognosis is good. Complete recovery is generally achieved within 6 ⫺12 weeks. However, fatigue can per- sist for 8 to 9 months, which for athletes, for example, means an inability to train, resulting in a drop in per- formance. In this context, it has been suggested that the fatigue syndrome may indeed be caused by a variant of EBV. • In rare cases, a fulminant course, possibly even with a fatal outcome, is witnessed. In so-called sporadic fatal infection, the mortality rate is relatively high (40 ⫺45%).

A chronic course of EBV infec- tion has been observed in some families, implying a genetic predisposition. Transition into chronic hepatitis or cirrhosis need not be feared because it is extremely rare.

In 50 ⫺70% of cases, an EBV infection de- veloped following liver transplantation, and in 2% of these patients, EBV hepatitis occurred, sometimes with a lethal outcome.

• Therapy is symptomatic. Treat- ment with aciclovir is reported to be without success. In complicated courses, erythromycin (cave ampicillin!) and glucocorticoids may be indicated.

1.1.2 Herpes simplex hepatitis

The herpesvirus hominis is a generally widespread virus which can affect all tissues. Herpes simplex virus types 1 (mostly systemic) and 2 (genital herpes) are transmit- ted by droplet or smear infection. • In newborns, in patients with a weakened immune response or in im- munosuppression (particularly following liver trans- plantation or in AIDS) as well as in chronic diseases (for example colitis) and during pregnancy, the course of disease may be severe, even lethal. • The viraemia can also cause herpes hepatitis. Clinical findings include fever, fatigue, abdominal discomfort (ca. 60%), hepato- megaly (ca. 35%), leucopenia and thrombopenia, marked increases in transaminases and occasionally dis- tinct decreases in cholinesterase and albumin. Jaundice tends to be rare (with a value of < 5 mg/dl). Diagnosis can be established serologically by detecting herpesvirus antibodies of the IgM class or by demonstrating the presence of pathogens. Mucocutaneous changes are infrequent. The liver surface usually displays variable, yellow-coloured focal necrosis with red borders. • Histo- logically, microvesicular fatty degeneration is detectable;

focal hepatic necroses are surrounded by hepatocytes with intranuclear inclusion bodies of Cowdry type A (surrounded by a bright area) (s. fig. 23.2) or type B (homogenous, ground glass-like).

Fig. 23.2: Acute herpes virus hepatitis with intranuclear bodies (Cowdry type A) (씮)

The extent ranges from individual cell necroses to patchy confluent lobular necroses with irregular zoning.

HSV are directly cytopathic; thus cellular necroses appear at first, followed by inflammatory infiltrates.

Herpesviruses are visible by electron microscopy; they can be cultured from the liver and rendered visible through staining by means of immunoperoxidase. • The prognosis is dubious in high-risk patients; mortality is 10 ⫺15%. Following severe fibrosis resulting from long- standing protracted HSV hepatitis, chronic cholestasis may develop (even with a lethal course). There have been several reports of a fulminant course of disease.

(24, 27, 30⫺34, 36)

• Therapy is effected, even during preg-

nancy, using aciclovir as the agent of choice with

5( ⫺10) mg/kg BW/8 hours as i.v. infusion or, in severe and immunosuppressed cases, with 10 mg/kg BW. Gan- ciclovir has also proved to be effective with 2 mg/kg BW/12 hours as i.v. infusion.

1.1.3 Herpesvirus hepatitis

A particular hepatotropicity causing severe herpes hepa- titis is ascribed to herpesvirus 6 (HHV-6). There have even been reports of a fulminant course with this virus infection.

• HHV-8 causes Kaposi’s sarcoma.

The liver is the most common site, with dark reddish- violet tumour nodes. Histological analysis reveals endo- thelial cell proliferations and growths of spindle-shaped fibroblast-like cells. The bile ducts may be altered.

Transaminase levels are elevated, and jaundice occurs.

There may be a causal relationship between HHV-8 infection and multicentric Castleman’s disease. The latter usually implies the presence of peliosis hepatis, perisi- nusoidal fibrosis and nodular regenerative hyperplasia.

1.1.4 Varicella-zoster hepatitis

“Chickenpox” in infancy and “shingles” in adults are caused by the same varicella-zoster virus. Very rarely and almost exclusively in immunosuppressed patients, concomitant hepatitis can occur with pronounced (mainly focal) hepatocellular necrosis, sometimes even with a fatal course.

Leucocytic portal and periportal infiltration can spread to the blood vessels and bile cap- illaries. Intranuclear inclusion bodies are present (s. fig.

23.2). Diagnosis is based on increased GPT, GOT, GDH and γ-GT values as well as the presence of vari- cella IgM antibodies; alternatively, pathogens can also be demonstrated in cultures. In children, a differential diagnosis of Reye’s syndrome must be considered. As therapy in a severe course, aciclovir is indicated.

Fig. 23.3: Herpes zoster. Pronounced concomitant hepatitis: GPT 186 U/l, GOT 132 U/l, GDH 8.3 U/l,γGT 56 U/l, cholinesterase 앗;

alkaline phosphatase and bilirubin normal

Herpes zoster generally shows less severe concomitant viral hepatitis. In one particular case of zoster disease (s. fig. 23.3), we observed an unusually pronounced

form of hepatitis. After recovery, the patient revealed normal laboratory values.

1.1.5 Cytomegalovirus

A cytomegalic infection is transmitted perinatally or postnatally (mainly unnoticed) by the cytomegalovirus (CMV) ⫺ a DNA herpesvirus ⫺ as well as by direct body contact (droplet-smear infection, breast milk, sexual intercourse) and blood transfusion. Some 60 ⫺80% of all adults in the USA and in Europe have overcome a cyto- megalic infection and are now immune.

In terms of liver involvement, a pre-/perinatal infection usually causes hepatosplenomegaly, moderate jaundice (ca. 60%), differing degrees of cholestasis (concomitant cholangitis) and mild cytomegaly hepatitis. In numerous cases, the characteristic intranuclear inclusion bodies (so- called owl’s eyes) can be found. The occurrence of giant- cell hepatitis (s. fig. 22.5) is considered to be an unusual event. Occasionally, granulomatous hepatitis with epi- thelioid cellular or histiocytic granulomas occurs. His- tologically, the hepatic changes can persist for months or years. Therefore, non-cirrhotic portal hypertension may develop.

Mortality is about 20%.

Postnatal infection, providing it does not take a symp- tom-free course, displays the clinical picture of infec- tious mononucleosis with similar haematological find- ings and complicative developments (such as haemolytic anaemia, thrombopenic purpura, pneumonia) as well as retinitis, arthritis, acute portal vein thrombosis and col- itis. In about 25 ⫺35% of cases, cytomegaly hepatitis develops with moderate jaundice, hepatomegaly, a slight increase in transaminases and varying degrees of chole- stasis. Cytomegaloviruses can persist in lymphocytes and other body cells and may be reactivated under con- ditions of diminished immunity or immunosuppression.

In infancy, cytomegalic infection is mainly symptom-

free. Up to 40% of cases, however, did show evidence of

cytomegaly hepatitis with hepatomegaly. Virus excretion

in the urine points to viraemia. • In adulthood, there is

likewise evidence of concomitant hepatitis

as well as

granulomatous hepatitis

in addition to the gen-

erally pronounced cytomegalic infection, which is wit-

nessed to varying degrees during this phase of life. Mod-

erately increased GPT, GOT, GDH and LDH activity

is generally in evidence; this is sometimes accompanied

by a distinctly pronounced elevation of γ-GT (without

an equivalent rise in AP) and decreased levels of serum

iron. Occasionally, marked cholestasis occurs. In most

cases, there is a reduction in serum iron. Bilirubin values

are moderately elevated or completely normal.

•

Diagnosis of cytomegalic infection is based on the anti-

body titer increase of CMV IgM (sometimes with reacti-

vation), detection in the virus by PCR, virus excretion in

urine or in situ hybridization. Histologically, the typical

intranuclear inclusion bodies suggest a cytomegalic

infection.

CMV infection is to be feared in the

Acute concomitant viral hepatitis

liver transplant; thus there is a danger of “vanishing bile-duct syndrome”.

• Therapy consists of gan- ciclovir

or foscarnet. CMV immunoglobulin is recommended for pre-exposure prophylaxis.

1.2 Togaviruses 1.2.1 Rubella hepatitis

Connatal infection due to the 60 nm RNA virus, which belongs to the togavirus group, is accompanied by a clearly enlarged liver and spleen as well as, on occasions, by jaundice. Histologically, cholestasis with bile pigmen- tation in the hepatic cells and with bile thrombi in the canaliculi is found. The portal fields are widened and irregular as a result of inflammatory infiltration, and the ductuli generally display pronounced proliferation.

Occasionally, giant-cell hepatitis occurs. (s. fig. 22.5) • In adolescents and adults, granulomatous hepatitis is some- times observed. In other cases, only slight histological changes are detectable, or the findings can be interpre- ted as insignificant non-specific reactive hepatitis. In the later stages, fine calcification foci can develop (as in Ebola hepatitis).

(s. fig. 21.1)

1.2.2 Spring-summer encephalitis hepatitis

In spring and summer, ticks (especially Ixodes ricinus) can transmit meningo-encephalitic viruses of the toga- virus family to human beings. During this disease, con- comitant hepatitis may develop, with a moderate increase in transaminases. Histologically, pronounced focal hepatic cell lesions are found together with mesenchymal inflammatory reactions; all of these findings are attribut- able to non-specific reactive hepatitis.

1.3 Picornaviruses 1.3.1 Coxsackie hepatitis

This virus species derived its name from the town of Coxsackie in the state of New York, where virological evidence thereof was successfully obtained for the first time. Coxsackie viruses are assigned to the picornavirus group, consisting at present of 23 A and 6 B types. • Coxsackie hepatitis with mesenchymal reactions, portal infiltration and focal hepatocellular necrosis sometimes occurs, especially in infants. Cholestatic, predominantly centrolobular forms of the disease, can develop in adults. A lethal course is extremely rare.

• The course of infection with the Coxsackie type B 4 or B 5 virus may give rise to the Fitz-Hugh-Curtis syndrome with the development of the typical violin string-like adhesive strands.

(s. fig. 24.2)

1.3.2 ECHO virus hepatitis

The widespread group of echoviruses, with its 31 known serotypes, has not yet been reliably categorized system-

atically or pathogenically. These viruses can also give rise to concomitant hepatitis, with type 4 and type 9 being held mainly responsible for this condition.

1.4 Paramyxoviruses 1.4.1 Measles hepatitis

The measles virus, discovered in 1911, is a large (100 ⫺150 nm) paramyxovirus with a lipid envelope.

Concomitant measles hepatitis occurs in 80% of all adults suffering from measles. It generally takes an anic- teric, clinically bland course, and in most cases even goes unnoticed. Diagnosis is based on the elevation of transaminases and the detection of IgM antibodies.

Cytologically, multinuclear giant cells are found in the nasal secretion. The prognosis for measles hepatitis is good. Despite lifelong immunity, however, the measles virus is able to persist latently in cells, especially in lym- phocytes (as in autoimmune hepatitis).

1.4.2 Parotitis hepatitis

The parotitis virus, an RNA virus of the paramyxovirus group, can also cause mumps hepatitis with correspond- ing minimal histological and laboratory findings.

1.4.3 Giant-cell hepatitis

In 1991 in Canada,

determined the pres- ence of paramyxoviruses in patients with an infaust course of giant-cell hepatitis: out of 10 patients, only 5 survived with the help of liver transplantation. Para- myxovirus nucleocapsid protein, with a diameter of 12 ⫺17 nm, was detected in the cytoplasm of the hepato- cytes.

Until then, this paramyxovirus had been unknown. It can cause severe acute hepatitis, which might even be fatal.

(s. p. 417!)

1.5 Adenovirus hepatitis

Adenoviruses can be the cause of hepatitis in newborns or immunosuppressed persons, sometimes even with a fulminant course. They bring about the formation of inclusion bodies in the hepatocellular nuclei. Adeno- virus infections can be diagnosed either serologically or by virus isolation.

1.6 Human parvovirus B19

HPV B19 causes erythema infectiosum in children. It may also lead to acute hepatitis. Aplastic anaemia is found in adults with simultaneous, potentially massive liver cell necroses and fulminant liver failure. HPV B19 can be detected in the liver tissue using PCR.

1.7 HIV hepatitis

By means of virological examination methods, it was

possible to demonstrate HIV-1 RNA in hepatocytes,

Kupffer cells and endothelial cells. The liver may be involved in systemic HIV disease both during primary infection and in the more advanced stages. The eleva- tion of the transaminases, of GDH and γ-GT is highly significant. Hepatomegaly can occasionally be detected as well and is attributed to infection-related hyperplasia of the liver cells. HIV-concomitant hepatitis shows differ- ing degrees of focal hepatocellular necrosis, inflam- matory mesenchymal reactions, portal field infiltration, granulomas or peliosis hepatis. During the course of HIV infection, HIV cholangiopathy, frequently of the sclerogenic type, may also develop. Cryptosporidiosis of the bile ducts with cholangitis has so far only been observed in AIDS. (s. p. 639) • The most common opportunistic infective agents are Mycobacterium avium intracellulare (40 ⫺45%), cytomegalovirus (20⫺30%), cryptosporidium and various mycoses (histoplasmosis, cryptococcosis, coccidiomycosis).

2 Exotic hepatotropic viruses

A large number of virus species that can be found in tropical and subtropical countries are known to be hepatotropic pathogens. They can give rise to minimal findings of so-called non-specific reactive hepatitis or fatty degeneration of the liver cells with cell necrosis, or may be the cause of severe liver disease. All of them have been categorized under the generic term exotic virus diseases.

They are pathogens from the family of (1.) flaviviruses, (2.) filoviruses, (3.) arena- viruses, and (4.) bunyaviruses. (s. tab. 23.2)

1. Flaviviruses

앫 yellow fever D E

앫 dengue fever D E

앫 Kyasanur Forest disease D E

앫 Semliki Forest disease (alphavirus) D E 2. Filoviruses

앫 Marburg virus S D E

앫 Ebola virus S D E

3. Arenavirus

앫 Lassa fever S D E

앫 Bolivian haemorrhagic fever 4. Bunyaviruses

앫 Hantavirus D E

앫 Rift Valley fever (Phlebovirus) D E 앫 Crimea-Congo fever (Nairovirus)

Tab. 23.2: Significant exotic hepatotropic viruses which can cause hepatic damage. • In Germany, the obligation for notification is given in cases of suspicion (S), disease (D) or exitus (E). This can, however, vary from country to country. If in doubt, contact the Public Health Department!

2.1 Yellow fever

The main epidemic regions are South America and equatorial Africa, i. e. the so-called yellow fever belt between the 15

northern latitude and the 15

southern

latitude. The yellow fever virus is transmitted from human being to human being by infected mosquitoes, especially Aedes aegypti or Aedes simpsoni. There is a marked steatosis hepatis. Often a bacillary peliosis hep- atis is found; it can be associated with the cutaneous bacillary angiomatosis. Rochalimaea henselae have been determined as a pathogen. In children with a coinfec- tion of HIV and adenoviruses, fulminant hepatitis has been reported. An incubation period of 3 ⫺6 (⫺13) days is followed by fever with viraemia, jaundice, hepato- splenomegaly, arthralgia, myalgia, exanthema, bleeding and haematemesis (“vomito negro”) as well as circula- tory disorders and renal damage (largely in the form of fatty tubular degeneration). However, inapparent or bland courses of disease are equally possible.

Hepatic lesions in the case of yellow fever are more likely to correspond to those of hepatosis. (s. p. 404) There is also evidence of distinct acidophilic hepatocellular necro- sis as well as microvesicular fatty degeneration of the hepatocytes. Hyaline, eosinophilic inclusions in the cyto- plasm of degenerated hepatic cells (so-called Councilman bodies) are characteristic and were first identified by

Councilman

in 1890 in yellow fever (s. p. 396). Acidophilic inclusion bodies in the hepatocellular nuclei which are arranged concentrically around the nucleolus (so-called Torres corpuscles) correspond to the yellow fever virus

(C. M. Torres, 1928)

. The liver does not present any signifi- cant signs of inflammation. The reticular fibre structure is maintained, so that the liver architecture is usually completely restored-provided the outcome of the disease is favourable. (s. fig. 23.4)

Fig. 23.4: Portal inflammation and acute parenchymal necrosis (N) due to shock (first periportal cell trabecula is still intact). Clinical diagnosis: yellow fever

The diagnosis is established by determining the specific

YF IgM antibodies and/or the virus RNA. Laboratory

parameters reveal an elevation of the transaminases,

GDH, γ-GT and LDH as well as a reduction in leuco-

cytes, Quick’s value and cholinesterase. Albuminuria is

also present. Mortality (5 ⫺10%) is generally due to

renal insufficiency. After recovery, immunity is lifelong.

Acute concomitant viral hepatitis

Chronic courses of disease are not known. When travel- ling to yellow fever regions, immunization (with live vac- cine) is imperative; vaccine protection lasts for 6 ⫺10 years. (s. p. 451)

2.2 Dengue fever

The dengue virus is also related to the flavivirus species.

It is transmitted by mosquitoes (of the Aedes type). The prognosis is relatively good ⫺ despite the fact that several hundred deaths have been recorded during epi- demics (such as in Java and India in 1996). Altogether, some 55 million people contract the disease every year.

The worldwide mortality rate is approx. 10%. In Ger- many, more than 1,500 cases of infection are registered annually. Following a 5 to 8 day incubation period, the clinical picture comprises fever (“breakbone fever”), headache, nausea, haemorrhage (haematuria, melaena), myalgia and arthralgia, exanthema, lymphadenopathy, and even splenic rupture. • Concomitant hepatitis of dif- ferent degrees of severity, often with centroacinar necro- sis and microvesicular steatosis, can occur. Fulminant hepatitis is rare. Convalescence is protracted. Diffuse residual parenchymal calcifications may remain. No vaccine has been found so far.

2.3 Marburg virus disease

In 1967 in Marburg (Germany), a total of 23 patients contracted a previously unknown infection caused by the “Marburg virus”, which belongs to the filoviruses.

Altogether, five outbreaks have been reported, with over 120 cases. It is a single-strand RNA virus, 790 ⫺970 nm in length and 80 nm in width. Infection resulted from direct, work-related contact with African apes (green guenons) as well as human transmission (partially due to sexual contact). After a 5 to 7 day incubation period, the clinical picture became serious, with fever, vomiting, diarrhoea, exanthema, conjunctivitis, myalgia, haemor- rhagic diathesis with thrombopenia, renal and hepatic damage as well as disorientation. • Laboratory param- eters and histological examinations pointed to severe hepatitis with hepatosplenomegaly. Jaundice is ex- tremely rare. Hyaline eosinophilic liver cell necrosis, microvesicular fatty degeneration and lymphomono- cytic infiltration of the portal fields predominate. The patchy necroses tend to merge and form bridging necro- ses. Basophilic bodies can be found in the necrotic cells.

The reticular fibre structure remains intact. • The prog- nosis is unfavourable: in the Marburg epidemic, mortal- ity was 28%; in epidemics in the Sudan and in Zaire, it was 53% and 88%, respectively.

2.4 Lassa haemorrhagic fever

Lassa fever was first identified in 1969 in a missionary in Lassa (Nigeria).

The disease is also endemic in

eastern Sierra Leone. Over 100,000 people worldwide contract the disease every year. A single-strand RNA virus of the arena group was isolated and character- ized as the pathogen.

The disease is transmitted by rats. The incubation period is 3 ⫺16 days. • It manifests as haemorrhagic fever with ulcerous inflam- mation in the throat and mouth cavity, arthralgia, exanthema, alopecia, hearing impairment, lymph- adenopathy as well as haemorrhages. In endemic areas, diagnosis is generally based (approx. 80% of cases) upon the triad (1.) fever and pharyngitis, (2.) proteinuria, and (3.) retrosternal pain. • The liver dis- plays distinct acidophilic necrosis, frequently bridging necroses, and bleeding. Pronounced Kupffer-cell hyper- plasia is evident. Deposits of lipofuscin are found.

The transaminases and GDH are markedly increased;

the blood count shows leucopenia and thrombopenia.

The course is anicteric as a rule. Hepatosplenomegaly is present. The diagnosis is confirmed by the presence of IgM antibodies. Mortality is 35 ⫺40%. Ribavirin has proved successful as therapy. There is still no vaccine available.

2.5 Ebola haemorrhagic fever

The Ebola virus disease was first observed in 1976 in Sudan (in the vicinity of the Ebola River). Altogether, 14 outbreaks have been reported. Apart from in Sudan, Ebola infections are frequent in the Congo and in Gabun. The incubation period is 7 ⫺10 days. Both the course of disease and the virus itself closely resemble the Marburg virus, although it is a virus in its own right and related to the filovirus species. Clinical findings include generalized pain, pharyngitis, conjunctivitis, bronchitis, exanthema and enanthema. Death usually occurs on the ninth day. The mortality rate of this haemorrhagic fever with pronounced hepatic damage (focal necrosis) was between 51% and 89%.

(s. fig. 23.5)

Fig. 23.5: Portal (left) and parenchymal (right) round-cell inflam- mation. Clinical diagnosis: Ebola fever

2.6 Rift Valley fever

This severe, febrile clinical picture was first observed in 1930 in Africa, predominantly in Rift Valley (Kenya).

The causative pathogen is a bunyavirus, transmitted to both animals and humans by mosquitoes. While it is generally fatal in animals, especially in sheep, the prog- nosis in humans is favourable; its course resembles that of influenza. Liver findings show concomitant hepatitis.

(107, 109)

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