Acute virus

In chronic diffuse infections steady-state infections , all of the cells are infected and both virus and cell multiplication proceed without the cells being killed. Virus is continually released from the cells, and the infection cannot be eliminated by antiviral antibodies.

The third type is the so-called true latent infection, in which the viral genome is replicated and segregated to the daughter cells either within the chromosomes or extrachromosomally. Persistent infections are caused by a wide variety of viruses through diverse pathogenetic mechanisms that may cause strikingly different diseases see Chs. Although the mechanisms by which any of these viruses produce persistent infection are not completely understood, some common factors have been identified.

The first is immune modulation. Many viruses that cause persistent infection avoid the specific and nonspecific immune defenses in several ways. Examples include:. Limitation of recognition molecules on infected cells: a. Restricted expression of viral antigens e. Antiviral antibody-induced internalization and modulation of viral antigens e. Blocking antibody that prevents the binding of neutralizing antibody e. Decreased expression of cell major histocompatibility complex recognition molecules e.

Altered lymphocyte and macrophage functions, including modified production of cytokines and immunosuppression e. Infection in immunologically privileged anatomic sites e.

The second factor is modulation of viral gene expression. Examples include down regulation of some viral genes by viral or cellular regulatory gene products e. Further work is being directed toward defining the relative importance of various mechanisms in the initiation and maintenance of persistent viral infections. For disease to recur in a latent infection the virus must be reactivated and begin replicating.

Some factors associated with reactivation are infection with other viruses as in HIV , nerve trauma e. Papovavirus encephalitis in immunosuppressed patients may represent exacerbation and spread of a chronic infection. A number of viruses can infect cells of the lymphoid system during acute infection, and some of these viruses persist Table Thus, the lymphoid system also may serve as a reservoir for seeding other organs with the persisting virus.

Persistent infection of the immune system may lead to evasion of immunologic surveillance. A variety of immune cells e. The long lag time between infection and development of AIDS is called clinical latency. There are two early levels of restriction in HIV gene expression. The second is influenced by the levels of the HIV regulatory proteins Tat, Rev derived from multiply spliced mRNA that determine the fate of the initiated viral transcript by promoting more efficient elongation of initiated viral mRNA tat and by preventing the splicing that promotes translation of the viral structural proteins rev and production of genomic RNA see Ch 62 and Fig.

Host regulatory mechanisms also are important in modulating HIV expression and replication. The transition from a latent to a productive infection may occur in response to cytokines e.

Proposed mechanisms for persistence and escape of immune surveillance by HIV-infected cells include:. Avoidance of neutralizing antibodies by spreading directly from cell to cell. Budding of virus particles into cytoplasmic vacuoles, resulting in masked virus production. Infection by these viruses is followed by a to year clinically latent period before development of leukemias or neurologic disorders in a minority of infected individuals.

The few cells containing truly latent provirus escape the immune surveillance because HTLV expression is efficiently down regulated as a result of DNA methylation and a lack of protein-protein Tax-CREB interaction or appropriate transcription factors in quiescent T cells.

After the initial EBV infection and replication in epithelial cells e. In these cells, the virus is truly latent, but when it is reactivated, infectious immortalizing virus is produced. The estimated frequency of EBV-carrying cells in healthy individuals varies from 20 to per 10 7 B cells. Immortalized B cells obtained by in vitro infection of normal cells are a well-studied model for latent EBV infection.

EBV-seropositive healthy individuals maintain humoral and cellular immunity against these latent proteins, suggesting that immortalized EBV lymphoblasts can occur and persist for long periods of time in vivo.

Since virus-specific antigens are present in the membrane of latently infected B cells, it is appropriate to examine how these cells escape immune surveillance. These cells were not killed by MHC-matched, virus-specific cytotoxic lymphocytes CTLs in assays in which EBV-transformed B lymphoblastoid cells derived from the normal B cells of the patients were readily lysed. Therefore, the initial interaction that normally occurs between CTLs and target cells does not take place, and the infected cells may survive, even though they express class 1 major histocompatibility complex molecules and the EBV-encoded latent membrane proteins.

The strongest evidence for the existence of latent CMV infection comes from the increased incidence of reactivated infection in seronegative individuals who undergo transplants of organs from seropositive donors or in immunosuppressed AIDS patients.

CMV is well known to infect multiple organs, including the salivary glands, lung, gastrointestinal tract, kidney, liver, spleen and brain. However, all the cell populations that harbor latent CMV have not been adequately defined. The best candidate cells for latent infection are thought to be monocytes.

During persistence CMV appears to impair immune responses at several levels: a altered expression and intracellular distribution of antigen-presenting molecules such as MHC class I; b altered production of lymphocyte adhesion e. In addition, both viruses are often detected in saliva.

Also, both viruses are reactivated in individuals receiving immunosuppressive therapy or with immune disorders, such as AIDS. Many chronic, degenerative nervous system diseases are related to viral persistence Table Persistence in the nervous system probably involves some unique mechanisms that take advantage of the many types of specialized cells and the immunologically privileged status of the central nervous system.

During acute herpes simplex virus HSV infection see Ch. In the sensory ganglia, the virus may cause a cytolytic infection or establish a latent, noncytolytic infection. Sympathetic ganglia and other cell types of the central nervous system may also serve as sites of virus latency.

In the neuron, viral DNA is maintained as an extrachromosomal plasmid episome with 1 to 20 copies per cell. Current studies are examining the possibility that latent virus is restricted by virus DNA-encoded antisense RNA molecules known as latency-associated transcripts LATs. Reactivation of latent infection and an associated down regulation of the LAT promoter, often occurs after various stress-related stimuli, e.

When the latent virus is reactivated, its genome passes anterograde in axons to the epithelium, where productive replication takes place Fig. Establishment and reactivation of latent herpesvirus infections. A Establishment of herpes simplex virus or varicella-zoster virus latency in ganglia after primary infection of skin or mucosa.

B Reactivation of virus in ganglion and spread through more After recovery from acute varicella chickenpox , the virus establishes latency in multiple ganglia of the human neuraxis Fig. Years later, the virus may reactivate, and the distribution of lesions in the skin corresponds closely to areas of innervation dermatome from an individual dorsal root ganglion Fig. However, in immunocompromised patients, life-threatening disseminated infections can occur. In these cells, limited transcription may take place from some, but not all, of the immediate early and early genes of the latent viral genome.

Thus, expression of latent varicella-zoster virus genes appears to be different from that of HSVs. Where mainly non-polyadenylated LATs that are antisense to immediate early transcripts are expressed and accumulate in neuronal cells. VZV-encoded LATs are polyadenylated transcripts of the sense direction that have a short half-life and are detectable in non-neuronal, satellite cells and in ganglia as well.

However, there is no significant viral protein synthesis detectable from the polyadenylated transcripts during latency. The molecular basis of latency and reactivation of latent virus has not been fully characterized.

Measles is normally an acute self-limited disease in which the virus appears to be eliminated. In rare individuals, however, virus persists in the brain despite apparent humoral and cellular immune responses. Possible mechanisms of persistence include the immunologically privileged status of the brain, antiviral antibody-induced internalization of viral antigens, altered and restricted virus expression and replication as a result of mutations in the virus genome.

This persistent virus infection is manifested by progressive mental deterioration, involuntary movements, muscular rigidity, and coma see Ch. The inability of measles virus to complete its replication cycle is associated with a variety of transcriptional and translational anomalies which affect the expression, stability, or function of the matrix M , fusion F and hemagglutinin H genes.

In affected neurons there is an accumulation of inclusion bodies containing nucleocapsids, and surface proteins H, F and M. Virus-infected cells may avoid immune surveillance by mutation in the M protein encoding gene that may explain restricted production and budding of virus and syncytia formation in SSPE, which favors persistence.

SSPE patients have high titers of anti-measles antibodies in both serum and cerebrospinal fluid; however, antibody to M protein is often lacking. BK virus has been associated with hemorrhagic cystitis; however, the site of persistence is not known. The JC virus is thought to persist in the kidney, and is reactivated when the host immune system is impaired e. JC virus is regularly isolated from brain cells of patients with progressive multifocal leukoencephalopathy PML , a fatal demyelinating disease.

The mechanism of persistence for both viruses can be related to the encoded T antigens, which are functionally similar, but antigenically distinct from SV40 T antigen. The latent JC virus genome can randomly integrate into cellular DNA and, when excision of viral DNA is induced, the latent genome becomes activated, infectious virus is produced, and disease PML may develop.

The subacute spongiform virus encephalopathies are a unique type of slow virus infection caused by agents called unconventional viruses or prions see Ch. Many lines of evidence have converged to argue that these infectious agents are composed largely, if not entirely, of prion protein PrP molecules. Currently, the age group 40 and older have the highest rate of acute hepatitis B, related to the risk factors of injection drug use, multiple sex partners, and lack of prior vaccination.

Hepatitis C has been steadily increasing since , particularly in the 20 to 40 age group, thought to be secondary to injection drug use related to the opioid crisis and improved surveillance [14].

Again the majority of cases are in low-income regions [13]. The most severe complication of acute hepatitis is acute liver failure requiring liver transplantation and rarely occurs with data being reported only from liver transplant centers. These centers might select a sicker patient population and under-report patients who spontaneously recover or lack access to these specialized centers.

Given these limitations, the epidemiology of acute liver failure varies in different countries. The histopathology of acute hepatitis is determined by the underlying etiology causing the hepatocellular injury.

Acute hepatitis secondary to acetaminophen overdose demonstrates characteristic histological features such as central to central bridging necrosis and minimal inflammatory cell infiltrates.

The histopathology features of acute hepatitis secondary to viral infections usually show intranuclear viral inclusions and surrounding neutrophils. Classical historical features of autoimmune hepatitis demonstrate portal inflammation and interface hepatitis formally known as piecemeal necrosis which is essentially the presence of portal inflammatory cells between the portal and liver parenchyma [10].

Diffuse microvesicular steatosis, Mallory bodies, fibrosis, or cirrhosis of the typical findings seen in alcohol-related liver injury [18]. Iron accumulation with hepatocellular hemosiderin pigment and increase hepatic copper concentrations and liver biopsy samples are the classical histopathological findings in patients with hereditary hemochromatosis and Wilson's disease respectively [19]. PBC is characterized by classical findings of florid duct lesion which is essentially granulomatous and lymphocytic portal inflammation centered around the interlobular bile ducts.

The presence of concentric rings of fibrosis known as onion skin fibrosis is the hallmark historical features of PSC [20]. The clinical presentation of acute hepatitis depends on the underlying etiology. It can clinically manifest with various clinical signs and symptoms, ranging from asymptomatic elevated liver function tests to acute liver failure requiring liver transplantation.

Hence, ascertaining the etiology of acute hepatitis is of utmost importance in its clinical management, making it very crucial to obtain a detailed history that should include the duration of the presenting illness, travel history, and assessing for high-risk activities like IV drug use, alcohol consumption, sexual history, prior blood-product transfusion history, or recent food intake.

Patients with acute viral hepatitis commonly present with symptoms such as fever, malaise, fatigue, loss of appetite, vomiting, diarrhea, and abdominal pain.

Depending on the underlying etiology, physical exam findings can range from the presence of icterus and jaundice to signs of acute encephalopathy, seizures, bleeding diathesis, hypotension, and other manifestations related to multiple organ failure [5] [12].

Signs of chronic liver disease such as caput medusae, spider nevi, palmar erythema, ascites, Dupuytren contracture, gynecomastia, and hepatic encephalopathy can be seen in patients presenting with acute on chronic liver disease.

When evaluating patients with acute hepatitis, it is very important to distinguish between acute hepatitis and chronic hepatitis. The possible etiology and severity of the hepatocellular injury can be determined based on the abnormality of one or more of these biochemical tests that are involved in the performance of a specific liver function [1] [2] [3].

Also, it is very important to maintain suspicion for an extrahepatic process that could be contributing to abnormal liver function tests such as pregnancy, lactic acidosis, sepsis, and cardiac dysfunction. Although liver function tests give an initial idea about the possible etiology and severity of the underlying hepatocellular injury, further evaluation with specific diagnostic tests are recommended to ascertain the etiology of acute hepatitis. Based on the guidelines published by the American College of Gastroenterology ACG for the evaluation of patients with abnormal liver function tests [21].

The management of acute hepatitis depends on the specific etiological factor implicated in the acute injury to the hepatocytes. Hepatitis A and E are the most common infectious causes of acute hepatitis and usually have a self-limited clinical course, resolving in 2 to 4 weeks with supportive treatment that includes IV fluids, antiemetics, and symptomatic treatment.

Patients should avoid the use of alcohol and other potentially hepatotoxic medications and over the counter supplements but otherwise. They should also receive education about reducing the risk of transmission of infection to others [4]. Acute acetaminophen ingestion is a common noninfectious cause of acute hepatitis leading to acute liver failure and needs to be considered in all patients presenting with signs and symptoms of acute liver failure.

Prompt treatment with N-acetylcysteine should be initiated as early as possible after obtaining an initial history and acetaminophen testing. N-acetylcysteine can be administered orally or IV based on the clinical scenario as mentioned below. Treatment with N-acetylcysteine is also recommended for all patients with acute liver failure except ischemic hepatitis, with or without evidence of acetaminophen overdose.

The majority of the patient's with minimal symptoms and abnormal liver function tests and normal liver synthetic function can be evaluated as an outpatient or referred to hepatology. In patients with persistently elevated liver function with no clear identification of a specific etiology, further evaluation with a liver biopsy is warranted [2] [3] [21].

Infrequently, patients with acute hepatitis associated with acute liver failure characterized by hepatic encephalopathy and coagulopathy INR greater than 1. There are several criteria scoring tools e. Besides evaluating for the aforementioned causes of acute hepatitis caused by direct injury to the hepatocytes, other conditions causing secondary injury from extrahepatic or nonhepatic etiologies should also be considered on the differential diagnosis which includes choledocholithiasis, biliary or pancreatic malignancies, liver metastases, sepsis, systemic hypotension, hepatic artery thrombosis, congestive heart failure, etc [2] [12].

Prognosis of acute hepatitis depends on the etiology causing direct injury to the hepatocytes. Timely identification of the etiological agent causing acute hepatitis and the specific management is extremely important to reduce morbidity and mortality.

Although rare, the most serious complication of acute hepatitis is progression to acute liver failure ALF which is characterized by times increase in serum transaminases, hyperbilirubinemia, coagulopathy, and rapid onset of hepatic encephalopathy in patients without any prior liver disease [12] [15] [16].

The progression from acute hepatitis to acute liver failure depends on the underlying etiology. In low-resource countries, viral infections are the most common cause of ALF [12]. The specific etiology of acute liver failure is also an essential predictor for spontaneous recovery. Patients with acute liver failure should be considered for liver transplant and should be promptly transferred to transplant centers.

There are several prognostic screening tools for ALF and the assessment for emergent liver transplantation. Vaccinations for both hepatitis A virus and hepatitis B virus have been available since the s and have significantly decreased the incidence of these infections.

Hepatitis A virus gets transferred by fecal-oral contamination, and improved food handling, water purification, and improved hygiene will reduce the risk of spreading infection. The risk of contracting hepatitis B and hepatitis C infection can be decreased by avoiding IV drug use and safe sex practices.

Accidently toxic ingestion of acetaminophen by children can be reduced with safe storage practices out of reach from children and utilizing packaging that utilize childproof safety precautions. Also, in adults, unintentional toxic ingestion can be reduced with education about the many non-prescription products which contain acetaminophen.

For stable minimally symptomatic patients, if an etiology for acute hepatitis is not determined initially, then they need follow-up to monitor for the normalization of the liver tests or further evaluation if the abnormal test results continue.

Keys to remember and avoid in patients with acute hepatitis [23] :. Given the exhaustive conditions that can cause acute hepatitis, the management of this clinical condition requires an interprofessional, collaborative team approach that would aid in making a timely diagnosis resulting in appropriate management. Clinical presentation of acute hepatitis in patients can range from being asymptomatic with incidental abnormal liver biochemical test results to being critically ill with signs concerning for acute liver failure.

In clinical practice, acute hepatitis is primarily encountered by primary care physicians, emergency medicine physicians, and internists. Depending on the etiology and the severity, other specialists may need to be involved in the care team, including gastroenterologists, hepatologists, pharmacists, nursing staff, toxicologists, infectious disease specialists, transplant surgeons, intensive care teams, or liver transplant centers [15] [24]. In some instances of acute hepatitis caused by drug overdose or drug abuse, the involvement of behavioral health experts and substance abuse professionals is imperative.

Clinical pharmacists should thoroughly review the patient's medication profile and assist with appropriate drug dosing to prevent further insult from hepatotoxicity from drugs and drug-drug interactions. This book is distributed under the terms of the Creative Commons Attribution 4. Turn recording back on.

National Center for Biotechnology Information , U. Acute infections begin with an incubation period, during which the genomes replicate and the host innate responses are initiated. The cytokines produced early in infection lead to classical symptoms of an acute infection: aches, pains, fever, malaise, and nausea.

Some incubation periods are as short as 1 day influenza, rhinovirus , indicating that the symptoms are produced by local viral multiplication near the site of entry.

For some infections, incubation periods can last many days papilloma, days or even years AIDS, years. In these infections, the symptoms are likely produced by virus- or immune-induced tissue damage far from the site of entry.

An example of a classic acute infection is uncomplicated influenza. Virus particles are inhaled in droplets produced by sneezing or coughing, and begin replicating in ciliated columnar epithelial cells of the respiratory tract. As new infectious virions are produced, they spread to neighboring cells. Virus can be isolated from throat swabs or nasal secretions from day 1 to day 7 after infection. Within 48 hr after infection symptoms appear; these last 3 days and then subside.

The infection is usually cleared by the innate and adaptive responses in 7 days. However, the patient usually feels unwell for several weeks, a consequence of the damage to the respiratory epithelium, and the cytokines produced during infection. Acute viral infections are responsible for epidemics of disease involving millions of individuals each year, such as influenza and measles.

When vaccines are not available, acute infections are difficult to control — most are complete by the time the patient feels ill, and the virus has already spread to another host.

This characteristic makes it exceedingly difficult to control acute infections in large populations and crowded areas such as colleges, nursing homes, military camps. The outbreaks of norovirus gastroenteritis this winter — a classic acute infection — highlights the problem. Antiviral therapy cannot be used, because it must be given early in infection to be effective. There is little hope of treating most acute viral infections with antiviral drugs until rapid diagnostic tests are become available.

But the point is moot — there are no antivirals for most common acute viral diseases. The rapid clearance of acute viral infections is a consequence of robust host defenses.