Laboratory diagnostics of viral hepatitis. Medical tactic at viral hepatitis. HIV-infection. AIDS-associated infections and invasions.
http://intranet.tdmu.edu.ua/data/books/And-INF.pdf
Hepatitis A
Central to the prevention of any legal problem is establishing the correct diagnosis, which comes from a combination of careful history and subsequent examination. Appearances may be deceiving; therefore, always exclude drugs, particularly acetaminophen, as a cause of acute liver injury.
After establishing a diagnosis of hepatitis A virus (HAV) infection, tracing contacts and notifying local public health authorities are important steps for preventing further cases. Omitting these measures may place the practitioner in a vulnerable situation.
One important note is that the most common reason for misdiagnosis of hepatitis A is misinterpreting the serology tests.
Serologic Tests
Anti-hepatitis A virus immunoglobulin M
The diagnosis of acute HAV infection is based on serologic testing for immunoglobulin M (IgM) antibody to HAV. Test results for anti-HAV IgM are positive at the time of onset of symptoms and usually accompany the first rise in the alanine aminotransferase (ALT) level.
This test is sensitive and specific, and the results remain positive for 3-6 months after the primary infection and for as long as 12 months in 25% of patients. In patients with relapsing hepatitis, IgM persists for the duration of this pattern of disease. False-positive results are uncommon and should be considered in the event that anti-HAV IgM persists.
Anti-hepatitis A virus immunoglobulin G
Anti-HAV immunoglobulin G (IgG) appears soon after IgM and generally persists for many years. The presence of anti-HAV IgG in the absence of IgM indicates past infection or vaccination rather than acute infection. IgG provides protective immunity.
Liver Function Tests
Liver enzymes
Rises in the levels of ALT and aspartate aminotransferase (AST) are sensitive for hepatitis A. levels may exceed 10,000 mIU/mL, with ALT levels generally greater than AST levels. levels usually return to reference ranges over 5-20 weeks.
Rises in alkaline phosphatase accompany the acute disease and may progress during the cholestatic phase of the illness following the rises in transaminase levels.
Hepatic synthetic function
Bilirubin level rises soon after the onset of bilirubinuria and follows rises in ALT and AST levels. levels may be impressively high and can remain elevated for several months; persistence beyond 3 months indicates cholestatic HAV infection.
Older individuals have higher bilirubin levels. Both direct and indirect fractions increase because of hemolysis, which often occurs in acute HAV infection.
Modest falls in serum albumin level may accompany the illness.
Ultrasonography
Imaging studies are usually not indicated in HAV infection. However, ultrasonography may be required when alternative diagnoses must be excluded. The goals should be to assess vessel patency and to evaluate any evidence supporting the presence of unsuspected underlying chronic liver disease. Ultrasound scanning is essential in patients with FHF.
Other Tests
Liver biopsy has a minimal role in acute HAV infection. It may play a part in chronic relapsing HAV infection or in situations where the diagnosis is uncertain.
Other investigations (eg, serum acetaminophen) may be necessary, depending on findings from the history and clinical examination.
Molecular diagnostic techniques performed on blood and feces for HAV RNA are purely research tools at present.
Treatment
Treatment generally involves supportive care, with specific complications treated as appropriate. Liver transplantation, in selected cases, is an option if the patient has fulminant hepatic failure (FHF).
Patients at risk for developing acute hepatitis A virus (HAV) infection should undergo immunization for the virus. In addition, immunization of those at greater risk for morbidity from acute HAV infection is important.
A German study of immunization rates in patients with autoimmune liver disease identified that seroconversion rates in this population were lower; however, more importantly, the study identified that vaccination was not offered to a large proportion of this population. It is not difficult to identify a low risk-benefit ratio in patients with chronic liver disease, and the author would recommend vaccination for HAV in all who have no contraindication.
Supportive Care
For acute cases of HAV infection, therapy is generally supportive, with no specific treatment of acute uncomplicated illness. Locating the primary source and preventing further outbreaks are paramount. Initial therapy often consists of bed rest. The patient should probably not work during the acute phase of the illness.
Nausea and vomiting are treated with antiemetics. Dehydration may be managed with hospital admission and intravenous (IV) fluids. In most instances, hospitalization is unnecessary. The majority of children have minimal symptoms; adults are more likely to require more intensive care, including hospitalization.
About 3-8% of cases of FHF are caused by HAV; however, only 1-2% of HAV infections in adults lead to FHF. Refer patients with FHF to facilities with expertise in liver transplantation.
Acetaminophen may be cautiously administered but is strictly limited to a maximum dose of 3-4 g/day in adults. Other treatments are directed by specific complications.
Liver Transplantation
Patients with FHF are considered for liver transplantation. Recurrent disease after liver transplantation has not been reported. Patient selection for liver transplantation may be difficult, in that 60% of patients recover from FHF without needing the transplant (much as with acetaminophen toxicity), and predicting who needs this life-saving procedure is difficult.
Late referral has ominous implications, with the accompanying comorbidities (eg, renal failure, coagulopathy, cerebral edema) and waiting times contributing to poor outcomes.
Liver transplantation for chronic relapsing HAV infection has occurred in the context of decompensation with good results; however, there is a report of clinical recurrence after liver transplantation.
Postexposure Prophylaxis
Passive immunization with Gammagard reduces infection when administered within 14 days of exposure (ie, postexposure prophylaxis). Recommendations for providing postexposure prophylaxis are developed on the basis of risk.
Postexposure prophylaxis is recommended for nonimmunized close contacts of those recently diagnosed with acute HAV infection. The appropriate public health authority should be notified after diagnosis of HAV infection, and the process of contact tracing should be initiated. In the United States, as many as 10% of cases of acute HAV infection are seen in commercial food handlers. In any suspected food handler transmission, it is imperative that health department officials be notified immediately.
In many instances, preexposure prophylaxis has been somewhat replaced by immunization (see Immunization). For travelers, cost-benefit analysis suggests that vaccination is preferred over gamma globulin when an extended stay in the area of risk (ie, high endemicity) is longer than 3 months or when repeat travel to the area (ie, >2 visits outside a 3-mo period) is likely.
Immunization
Vaccination is highly effective at preventing HAV disease. The efficacy of the hepatitis A vaccine ranges from 80% to 100% after 1-2 doses compared to placebo. Current dosing recommendations are available (see Medication).
Immunization is indicated for individuals traveling to areas of high endemicity who have less than 2 weeks before departure. Both the vaccination and intramuscular (IM) immunoglobulin should be administered to provide long-term immunity, particularly in persons who intend to travel to these areas repeatedly.
People with chronic liver disease of any cause should consider hepatitis A vaccination. Response rates in patients with advanced liver disease and in those on immunosuppressive therapies are likely to be lower. The potentially disastrous outcome of acute HAV infection in this group cannot be overemphasized.
Hepatitis A vaccination in some low-risk groups who are potential sources of larger outbreaks of infection (eg, food handlers) has been implemented by some employers, although cost-benefit analysis for the employer does not seem to support such measures.
Epidemiologic studies of current and historical information related to hepatitis A infection patterns and risk factors show strong associations between socioeconomic improvement, increased water and sanitation, and decreasing HAV infection rates.
Areas in which a transition of epidemic hepatitis A (childhood acquisition very high) to endemic hepatitis A is occurring will likely lead to an increase in adult acquired infections and the morbidity associated with this in the absence of vaccination programs.
An excellent illustration of why this is likely is that the most prevalent risk factor for HAV acquisition in the United States is international travel. This study also lends further support to the importance of vaccination for international travelers. Hepatitis A is the most frequent vaccine-preventable disease in travelers, and it has the highest mortality and morbidity rates for any vaccine-preventable infection in travelers.
The global burden of acute cases of hepatitis A is changing and certainly is decreasing in Western societies. In the United States, vaccination programs targeting children during urban outbreaks have demonstrated significant benefits. Immunization programs applied to high-risk groups show morbidity and cost benefits. Approximately 20% of individuals with acute HAV infection may require hospitalization.
A 2012 Cochrane review of 9 studies including 732,380 participants reaffirmed the benefit of pre-exposure vaccination. Data from the review show that both the inactivated and live attenuated vaccines were effective for pre-exposure prophylaxis and that either vaccine provided approximately a 10-fold reduction in acute infections when compared to placebo. An interesting subgroup analysis of quality studies showed that if infections were to occur they occurred in the first year. In addition, pre-exposure prophylaxis was cost-effective and shared comparable risk of non-serious local and system adverse events in those receiving the inactive vaccine compared to those receiving the placebo. However, there were insufficient data on the safety of the live attenuated vaccine to render conclusions on safety and efficacy over time.
Global immunization appears to be prohibitively expensive. The hepatitis A vaccine is not yet licensed for use in persons younger than 2 years.
Diet and Activity
Encourage an adequate diet. Patients should avoid alcohol and medications that may accumulate in liver disease. Otherwise, no specific dietary restrictions are necessary.
Bed rest during the acute illness may be important, although data to support this practice are lacking. Restricting transmission is important, especially in the early phases of the illness. Returning to work should probably be delayed for 10 days after the onset of jaundice.
Prevention
Control at the source, with treatment of contacts to prevent further cases of disease is the primary goal. Long-term secondary goals include immunization, which increases herd immunity and reduces the likelihood of further outbreaks in high-risk communities. Education about transmission and prevention of transmission (eg, hand washing, safe food sources) is also important.
Hepatitis B
Laboratory evaluation for hepatitis B disease generally consists liver function tests (LFTs), including levels of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), alkaline phosphatase (ALP), total and direct serum bilirubin, and urine bilirubin and urobilinogen. Hematologic and coagulation studies include prothrombin time (PT), total protein level, albumin level, complete blood cell (CBC) count. In severe cases, serum ammonia levels may be obtained.
Acute hepatitis B disease
High levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), at a range of 1000-2000 IU/mL, is the hallmark of this disease, although values 100 times more than the upper limit of normal (ULN) can be identified. Higher values are found in patients with icteric hepatitis. ALT levels are usually higher than AST levels.
Alkaline phosphatase (ALP) levels may be elevated, but they are usually not more than 3 times the upper limit of normal.
Albumin levels can be slightly low, and serum iron levels may be elevated. In the preicteric period (ie, before the appearance of jaundice), leukopenia (ie, granulocytopenia) and lymphocytosis are the most common hematologic abnormalities and are accompanied by an increase in the erythrocyte sedimentation rate (ESR).
Anemia due to a shortened red blood cell survival period is an infrequent finding, although hemolysis may be noted. Thrombocytopenia is a rare finding. Patients with severe hepatitis experience a prolongation of the prothrombin time (PT).
Several viral markers can be identified in the serum and the liver. Hepatitis B surface antigen (HBsAg) (Australian antigen) and hepatitis B e antigen (HBeAg) (marker of infectivity) are the first markers that can be identified in the serum. Hepatitis B core antibody (HBcAb) (immunoglobulin M [IgM]) follows.
For patients who recover, seroconversion to hepatitis B surface antibody (HBsAb) and hepatitis B e antibody (HBeAb) is observed. The HBcAb is of the IgG class. Patients with persistent HBsAg for longer than 6 months develop chronic hepatitis.
Chronic inactive hepatitis B disease
Healthy carriers have normal AST and ALT levels, and the markers of infectivity (ie, HBeAg, HBV DNA) may be negative. HBsAg, HBcAb of IgG type, and HBeAb are also present in the serum.
Chronic active hepatitis B disease
Patients have mild to moderate elevation of the aminotransferases (≤5 times the ULN). The ALT levels are usually higher than the AST levels. Extremely high levels of ALT can be observed during exacerbation or reactivation of the disease, and they can be accompanied by impaired synthetic function of the liver (ie, decreased albumin levels, increased bilirubin levels, and prolonged PT).
Hepatitis B virus (HBV) DNA levels are high during this phase. HBsAg and HBcAb of IgG or IgM type (in case of reactivation) are identified in the serum.
If the AST levels are higher than the ALT levels, the diagnosis of cirrhosis must be excluded. Hyperglobulinemia is another finding, predominantly with an elevation of the IgG globulins. Tissue-nonspecific antibodies, such as antismooth muscle antibodies (ASMAs) (20-25%) or antinuclear antibodies (ANAs) (10-20%), can be identified. Tissue-specific antibodies, such as antibodies against the thyroid gland (10-20%), can also be found. Mildly elevated levels of rheumatoid factor (RF) are usually present.
Cirrhosis
In early stages of cirrhosis, findings of chronic viral hepatitis can be found. Later on, as the disease progresses, low albumin levels, hyperbilirubinemia, prolonged PT, low platelet count and white blood cell count, and AST levels higher than ALT levels can be identified. ALP levels and gamma-glutamyl transpeptidase (GGT) can be slightly elevated.
Radiologic Studies
Acute and chronic hepatitis B disease
Performing abdominal ultrasonography, computed tomography (CT) scanning, or magnetic resonance imaging (MRI) is important to help exclude biliary obstruction. Nonspecific findings include increased echogenicity of the liver parenchyma.
Cirrhosis
Imaging findings include coarse echogenicity of the liver, with a nodular appearance, and findings compatible with portal hypertension (eg, varices, splenomegaly, ascites, pleural effusion [ie, hepatic hydrothorax]).
Lesions can be detected and may be very difficult to evaluate, because they can be mistaken for regenerating nodules. In such cases, highly sophisticated techniques, such as MRI with superparamagnetic iron oxide (ferumoxides), should be considered. Ferumoxides (negative contrast material) are phagocytosed by the reticuloendothelial cells of the normal liver, producing predominant T2 imaging on MRI. Therefore, a marked decrease of the signal in the normal liver parenchyma occurs, effectively permitting the identification of tumors.
Liver Biopsy and Histologic Features
Liver biopsy, percutaneous or laparoscopic, is the standard procedure to assess the severity of disease for patients with features of chronic active liver disease (ie, abnormal aminotransferase levels and detectable levels of hepatitis B virus [HBV] DNA).
Although liver biopsy is not indicated for patients with acute hepatitis B disease, the findings are predominantly lobular, with degenerative and regenerative hepatocellular changes as well as accompanying inflammation. Necrosis may be predominantly centrilobular.
Ground-glass cells are seen in approximately 50-75% of livers affected by chronic HBV infection, and they stain positive for hepatitis surface B antigen (HBsAg) (see the image below). Immunohistochemical staining of the specimen can help identify the presence of HBsAg or hepatitis B core antigen (HBcAg) (ie, chronic infection).
Therapy is currently recommended for patients with evidence of chronic active hepatitis B disease (ie, high aminotransferase levels, positive hepatitis B virus [HBV] DNA findings, hepatitis B e antigen [HBeAg]). Various algorithms have been proposed, such as that by Keeffe and colleagues and the American Association for the Study of Liver Diseases (AASLD).
In general, for the HBeAg-positive patient population that is identified with evidence of chronic HBV disease, treatment is advised to be administered when the HBV DNA level is ≥20,000 IU/mL (105 copies/mL) and when serum alanine aminotransferase (ALT) is elevated for 3-6 months.
For the HBeAg-negative chronic population with hepatitis B disease, treatment can be administered when the HBV DNA is ≥ 2000 IU/mL (104 copies/mL) and serum ALT is elevated (ALT levels >20 U/L for females; 30 U/L for males) for 3-6 months.
Inpatient care
Patients with hepatitis B disease and fulminant hepatic failure should be hospitalized in the intensive care unit (ICU), and these individuals should be considered as liver transplant candidates in the event they do not recover.
Patients with acute hepatitis should be monitored with blood tests in order to document biochemical improvement.
Dietary limitations
For individuals with decompensated cirrhosis (prominent signs of portal hypertension or encephalopathy), a low-sodium diet (1.5 g/d), high-protein diet (ie, white-meat protein [eg, pork, turkey, fish]), and, in cases of hyponatremia, fluid restriction (1.5 L/d) are indicated.
Patients with acute and chronic hepatitis without cirrhosis have no dietary restrictions.
Pharmacologic Management
Currently, interferon alfa (IFN-a), lamivudine, telbivudine, adefovir, entecavir, and tenofovir are the main treatment drugs approved globally for hepatitis B disease, although ongoing trials are investigating new types of medications, such as tenofovir disoproxil in combination with emtricitabine, clevudine (l-FMAU), and therapeutic vaccines. It appears that lamivudine and telbivudine are not recommended as first-line agents in the treatment of hepatitis B disease.
Patients who have lost hepatitis B e antigen (HBeAg) and in whom hepatitis B virus (HBV) DNA is undetectable have an improved clinical outcome (ie, slower rate of disease progression, prolonged survival without complications, reduced rate of hepatocellular carcinoma [HCC], and clinical and biochemical improvement after decompensation).
Special attention must be given to patients on liver transplantation lists. Initiation of treatment with adefovir or entecavir or tenofovir or in combination with lamivudine is of cardinal importance before and after liver transplantation to achieve viral suppression and to prevent recurrence of the disease after the procedure.
Interferon alfa
Published reports indicate that after IFN-a treatment with 5 million U/d or 10 million U 3 times per week subcutaneously (SC) for 4 months, the HBV DNA levels and HBeAg become undetectable in 30-40% of patients. In addition, 10% of patients seroconvert from hepatitis B surface antigen (HBsAg) to hepatitis B surface antibody (HBsAb). Unfortunately, 5-10% of patients relapse after completion of treatment. A transient “flare” (ie, increased aminotransferase levels during the beginning of treatment) can be identified, and this represents the impact of the activated cytolytic T cells on the infected hepatocytes.
High levels of aminotransferases, a low viral load, and infection with the wild type are good prognostic factors for response to IFN-a treatment. However, Asian patients and patients with the precore mutant virus tend to not have a clinical response to IFN-a treatment.
Loss of hepatitis B surface antigen (HBsAg) indicates resolution of the HBV infection, acute or chronic, but is rare in chronic infection. A study by Tseng et al followed Taiwanese patients with chronic hepatitis B infection who developed spontaneous HBeAg loss (seroconversion). Patients with low levels of HBsAg a year after their seroconversion had a higher probability of loss of HBsAg.
Special attention must be given to patients with HBV-decompensated cirrhosis (eg, ascites, encephalopathy) who are taking IFN-a because of the fact that, although they occasionally may have a treatment response, these individuals can also deteriorate further.
The adverse effects of IFN-a treatment can sometimes be severe, even devastating. Some patients cannot complete treatment. A flulike syndrome, myelosuppression (eg, leukopenia, thrombocytopenia), nausea, diarrhea, fatigue, irritability, depression, thyroid dysfunction, and alopecia are among the adverse effects that may occur.
Pegylated IFN-a 2a
A 48-week regimen of pegylated IFN-a 2a (PEG-IFN-a 2a) might induce a 27% rate of HBeAg seroconversion and a 25% rate of loss of HBV DNA. Extension to treatment for 48 weeks resulted in an HBeAg seroconversion of 32%.
Placing patients that have HBeAg-negative chronic hepatitis B disease on 48 weeks of a PEG-IFN-a 2a regimen resulted in a significantly greater percentage of patients with a viral load that was nondetectable 24 weeks after the end of treatment (19%) compared with lamivudine monotherapy (7%).
It appears that patients infected by HBV genotype A or B have a better response to IFN treatment compared with patients infected by genotype C or D, and this kind of treatment appears to be more appealing, especially for patients with increased alanine aminotransferase (ALT) levels.
Lamivudine
A nucleoside analogue that inhibits the viral polymerase, lamivudine has been associated with a 4-log reduction of the viral load. Lamivudine treatment (100 mg/d) has also been associated with a 16-18% seroconversion rate from hepatitis B e antigen (HBeAg) to hepatitis B e antibody (HBeAb), a 30-33% rate of HBeAg loss, a 40-50% normalization of the value of the aminotransferases, and a 1-2% HBsAg seroconversion rate.
Histologic improvement (ie, reduction of histologic activity index of >2 points) has beeoticed in approximately 50% of patients taking lamivudine. The adverse effects are negligible.
Lamivudine appears to be effective for patients who do not have a treatment response to IFN-a (eg, patients infected by the precore mutant virus). A transient elevation of aminotransferases can be noticed shortly after starting treatment.
The HBeAg seroconversion rate has been shown to possibly increase to 27% after 2 years, 40% after 3 years, and 47% after 4 years of treatment in patients with a viral load of less than 104 pg/mL.
Lamivudine treatment has also been shown to dramatically improve the condition of patients with decompensated disease due to HBV reactivation.
The emergence of viral variants is the major complication in hepatitis B disease. Approximately 15-30% of patients develop a mutation of the viral polymerase gene (the YMDD variants) after 12 months of treatment, and approximately 50% develop a mutation after 3 years of treatment. However, continued treatment after the breakthrough with the variant type has been associated with lower HBV DNA levels, less aminotransferase activity, and histologic improvement. For these patients, discontinuation of treatment is accompanied by a reversion to a wild type of HBV and a flare of the disease.
Adefovir dipivoxil
Adefovir is a nucleoside analogue, a potent inhibitor of the viral polymerase. The efficacy of adefovir dipivoxil has been tested in HBeAg-positive, HBeAg-negative, and lamivudine-resistant patients with encouraging results.
The estimated rate of resistance to adefovir and the development of mutations (rtN236T and rtA181V) are approximately 4-6% after 3 years and approximately 30% after 5 years of treatment.
The optimal dose seems to be 10 mg/d. Higher doses are nephrotoxic.
The results of 2 multicenter trials that used adefovir for 48 weeks noted that in HBeAg-positive patients who received 10 mg of adefovir daily, there was a median 3.52 log reduction of the viral load (HBV DNA) level. In 48% of the patients, normalized aminotransferase levels were reported, and histologic improvement was seen in 53% of the patients who received this regimen. The HBeAg seroconversion rate was 12%.
Furthermore, of the HBeAg-negative population, 64% experienced histologic improvement after receiving 10 mg of adefovir for 48 weeks, and 72% had normalized aminotransferase levels. The serum HBV DNA level was decreased in 51% of subjects. The outcomes were maintained if treatment was continued for 144 weeks, but the benefits were lost if treatment was discontinued at 44 weeks. The development of resistant mutations (rtN236T and rtA181V) has been estimated to be around 6%.
Entecavir
Entecavir is a potent guanosine analogue inhibitor of the viral polymerase with 1.2% resistance in patients who have no history of previous treatment with nucleostide/nucleoside analogues and almost 56 % in lamivudine-resistant patients during a 6-year treatment period.
HBeAg-positive patients
With regard to the HBeAg-positive population, administration of 0.5 mg of entecavir in patients who are naive to nucleoside analogues relative to patients who received 100 mg of lamivudine for a duration of 48 weeks resulted in histologic improvement in 72% of the entecavir group compared with 62% of the lamivudine group. Undetectable serum HBV DNA levels were reported in 67% of entecavir-treated patients compared with 36% of lamivudine-treated patients.
Normalized ALT levels were achieved in 68% of the entecavir group versus 60% of the lamivudine group. The mean reduction in serum HBV DNA from baseline to week 48 was 6.9 log copies/mL (on a base-10 scale) in the entecavir-treated patients relative to 5.4 log copies/mL in the lamivudine-treated patients. HBeAg seroconversion occurred in 21% of patients treated with entecavir and 18% of patients treated with lamivudine.
HBeAg-negative patients
With regard to the HBeAg-negative population, administration of 0.5 mg of entecavir in patients who are naive to nucleoside analogues compared with patients who received 100 mg of lamivudine for a duration of 48 weeks resulted in histologic improvement in 71% of the entecavir group versus 61% of the lamivudine group. Undetectable serum HBV DNA levels were found in 90% of the entecavir-treated patients versus 72% of the lamivudine-treated patients.
Normalized ALT levels were achieved in 78% of the entecavir group compared with 71% of the lamivudine group. The mean reduction in serum HBV DNA levels from baseline to week 48 was 5.0 log copies/mL (on a base-10 scale) in the entecavir-treated patients versus 4.5 log copies/mL in the lamivudine-treated patients.
Complications
Complications from hepatitis B include progression to hepatocellular carcinoma (HCC), glomerulonephritis, and polyarteritis nodosa, as well as various dermatologic, cardiopulmonary, joint, neurologic, hematologic, and gastrointestinal (GI) tract manifestations.
Hepatocellular carcinoma
Even the presence of hepatitis B surface antibody (HBsAb) in the absence of hepatitis B surface antigen (HBsAg) or hepatitis B virus (HBV) DNA is significantly related to an increased risk for HCC. The annual incidence of this malignancy in patients with hepatitis B and cirrhosis reported in Taiwan is 2.8%. The estimated US annual incidence of HCC in patients infected with hepatitis B is 818 cases per 100,000 persons. Familiar clustering of HCC has been described among families with hepatitis B in Africa, the Far East, and Alaska.
HBV and HDV coinfection
The prevalence of hepatitis D virus (HDV) coinfection among patients infected with hepatitis B virus (HBV) worldwide is 0-20%. The speculation that HDV might promote hepatocarcinogenesis in these patients has been investigated. The prevalence of anti-delta among patients with cirrhosis with and without HCC was not significantly different. Therefore, delta superinfection does not appear to increase the rate of HCC.
HBV and HCV coinfection
The prevalence of HCC among patients with hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection is higher than in those with a single infection alone. The rate of development of HCC per 100 person years of follow-up is 2% in patients with cirrhosis and hepatitis B infection, 3.7% in patients with HCV infection, and 6.4% in patients with dual HBV and HCV infection. This points to a probable synergistic effect on the risk of HCC.
Possible pathogenic mechanisms
The mechanism by which chronic hepatitis B infection predisposes to the development of HCC is not clear. Cirrhosis is a cardinal factor in carcinogenesis. Hepatocyte inflammation, necrosis, mitosis, and features of chronic hepatitis are major factors for nodular regeneration, fibrosis, and carcinoma. Liver cell dysplasia, defined as cellular enlargement, nuclear pleomorphism, and multinucleated cells affecting groups or whole nodules, may be an intermediate step. The high cell-proliferation rate increases the risk for HCC.
The fact that facultative liver stem cells are capable of bipotent differentiation into hepatocytes or biliary epithelium, termed oval cells, may play an important role in the pathogenesis. These cells are small, with oval nuclei and scant pale cytoplasm.
Oval cells are prominent in actively regenerating nodules and in liver tissue surrounding the cancer. They appear to be the principal producers of alpha-fetoprotein (AFP). Although the cellular targets of carcinogenesis have not been identified, some evidence resulting from experimental animal models suggests that oval cell proliferation is associated with an increased risk for the development of HCC. Although cirrhosis is found in the majority of these patients, it is not obligatory, because chronic carriers may develop HCC even without the evidence of cirrhosis.
Glomerulonephritis
The most common type of glomerulonephritis described in association with hepatitis B is membranous glomerulonephritis (MGN), mainly in children. However, membranoproliferative glomerulonephritis (MPGN) and, even more rarely, immunoglobulin (Ig) A nephropathy, have been identified.
The prevalence rate of glomerulonephritis among patients with chronic hepatitis B is not well known, although observations have been made in children that suggest a range of 11% to 56.2%. However, such a high prevalence is not recognized in the United States, and this may be because of the differences in epidemiology of HBV, which might be predominantly perinatal in other geographic areas of the world.
A previous history of chronic liver disease is not present in the majority of these patients at presentation, and most of them have no clinical or biochemical findings to suggest acute or chronic liver disease. However, liver biopsies often demonstrate features of chronic hepatitis. Serologic markers of an HBV replicative state are often evident, and complement activation is suggested by low levels of C3 and C4.
Generally, the most prominent finding among affected children is MGN, primarily with capillary wall deposits of HBeAg. In contrast, adults present with features of MPGN with mesangial and capillary wall deposits of HBsAg. A rare overlap between membranous nephropathy and IgA nephropathy has also been described.
Possible pathogenic mechanisms
The mechanism by which patients with chronic hepatitis B develop glomerulonephritis is not completely understood. One possible explanation is that HBV antigens (ie, HBsAg, HBeAg) act as triggering factors, eliciting immunoglobulins and thus forming immune complexes, which are dense irregular deposits in the glomerular capillary basement membranes. HBV DNA has been identified by in situ hybridization in kidney specimens, distributed generally in the nucleus and cytoplasm of epithelial cells and mesangial cells of glomeruli and in the epithelial cells of renal tubules.
IFN-a therapy
IFN-a therapy has been successful in treating HBV-related glomerulonephritis. A regimen of 5 million units of IFN-a subcutaneously (SC) daily for 4 months has achieved HBsAg seroconversion with improvement of glomerulonephritis. It has also been reported that IFN-a given at a dose of 3 million units 3 times per week led to improvement of proteinuria only in patients with mesangial proliferative glomerulonephritis but not in patients with MPGN. Finally, a single case report described the resolution of this complication after liver transplantation.
Prognosis
The prognosis of renal disease in hepatitis B is related to several factors, such as age and response to therapy. Children with MGN have a more favorable response than adults. White persons have a better response than Asians and black patients. Approximately 30-60% of cases with MGN undergo spontaneous remission. However, the course of HBV-related membranous nephropathy in adults in areas in which the virus is endemic is not benign. Regardless of treatment, hepatitis B disease has a slow but relentlessly progressive clinical course in approximately one third of patients who have progressive renal failure, necessitating maintenance dialysis therapy.
Skin manifestations
A variety of cutaneous manifestations have already been recognized during the early course of viral hepatitis, among which are hives and a fleeting maculopapular rash. Women are more prone to developing cutaneous manifestations.
The various cutaneous lesions are episodic, palpable, and, at times, pruritic. Although they are transient, a discoloration of the skin can be identified after the resolution of the exanthem, particularly on the lower extremities.
Papular acrodermatitis, also recognized as Gianotti-Crosti syndrome, has been associated with hepatitis B, more commonly with acute infection in children.
Cardiopulmonary, joint, neurologic, hematologic, and GI tract manifestations
The following multisystem manifestations may occur in HBV:
- Pleural effusion, hepatopulmonary, and portopulmonary syndrome may occur in patients with cirrhosis
- Myocarditis, pericarditis, and arrhythmia occur primarily in patients with fulminant hepatitis
- Arthralgias and arthritis (serum sickness) subcutaneous nodules may also occur, but these are rare.
- Guillain-Barre syndrome, encephalitis, aseptic meningitis, and mononeuritis multiplex may occur in patients with acute hepatitis B
- Patients may develop pancreatitis
- Aplastic anemia is uncommon, and agranulocytosis is extremely uncommon
- Diffuse intravascular coagulation may occur in patients with fulminant hepatitis
Vaccination
Universal hepatitis B vaccination programs are ongoing in endemic areas, with encouraging results. The hepatitis B vaccine consists of recombinant hepatitis B surface antigen (HBsAg) produced in yeast. A series of 3 injections may achieve HBsAb levels greater than 10 million IU/mL in approximately 95% of people vaccinated. Vaccination with a single dose must be repeated every 5-10 years.
All newborns must be vaccinated against hepatitis B. For infants born to mothers with active hepatitis B, a passive-active (immunoglobulin [HBIG] and vaccination) approach is recommended.
Healthcare workers or people who have had a needle-stick accident from a patient with active hepatitis B infection must receive the active-passive immunization approach (HBIG and the first dose of the vaccine at the same time), and these individuals must be monitored with blood tests.
Current guidelines recommend all previously unvaccinated adults aged 19 through 59 years with diabetes mellitus (type 1 and type 2) be vaccinated against hepatitis B as soon as possible after a diagnosis of diabetes is made. Clinicians may use their discretion in determining whether to vaccinate elderly diabetic patients (≥60 years).
Low response rates have been associated with obesity, smoking, immunosuppression, and advanced age.
Approximately 25-50% of persons who initially do not have a vaccine response will show a response to 1 additional vaccine dose, and 50-75% of persons will have a response to a second 3-dose series.
A combined hepatitis A virus (HAV) and hepatitis B vaccine is licensed in many countries and offers the advantage of protection against both of these diseases at the same time.
The HBV vaccine seems to be safe, although some questions exist regarding neurologic complications.
Hepatitis C
Patients with acute hepatitis C virus (HCV) infection appear to have an excellent chance of responding to 6 months of standard therapy with interferon (IFN). Because spontaneous resolution is common, no definitive timing of therapy initiation can be recommended; however, waiting 2-4 months after the onset of illness seems reasonable.
Treatment of chronic HCV infection has 2 goals. The first is to achieve sustained eradication of HCV (ie, sustained virologic response [SVR]), which is defined as the persistent absence of HCV RNA in serum 6 months or more after completing antiviral treatment. The second goal is to prevent progression to cirrhosis, hepatocellular carcinoma (HCC), and decompensated liver disease requiring liver transplantation.
Antiviral therapy for chronic hepatitis C should be determined on a case-by-case basis. However, treatment is widely recommended for patients with elevated serum alanine aminotransferase (ALT) levels who meet the following criteria:
- Age greater than 18 years
- Positive HCV antibody and serum HCV RNA test results
- Compensated liver disease (eg, no hepatic encephalopathy or ascites)
- Acceptable hematologic and biochemical indices (hemoglobin at least 13 g/dL for men and 12 g/dL for women; neutrophil count >1500/mm3, serum creatinine < 1.5 mg/dL)
- Willingness to be treated and to adhere to treatment requirements
- No contraindications for treatment
A further criterion is liver biopsy findings consistent with a diagnosis of chronic hepatitis. However, a pretreatment liver biopsy is not mandatory. It may be helpful in certain situations, such as in patients with normal transaminase levels, particularly those with a history of alcohol dependence, in whom little correlation may exist between liver enzyme levels and histologic findings.
Patients with normal liver enzyme levels and minimal histologic damage noted on liver biopsy may elect to defer treatment until more effective and less toxic medications become available, whereas patients with more advanced liver injury may prefer to initiate treatment sooner. Patients should be informed that the treatment of HCV infection in the setting of normal liver enzyme levels remains controversial.
The treatment of hepatitis C has evolved over the years (see the following image). Initial studies used IFN monotherapy, but current treatments are combination therapy consisting of ribavirin and IFN or of IFN to which polyethylene glycol (PEG) molecules have been added (ie, PEG-IFN).
Evolution of the treatment of hepatitis C virus infection.
Protease inhibitors are emerging as a third feature of combination therapy. The first protease inhibitor indicated for use in HCV infection, boceprevir (Victrelis), was approved by the FDA in May 2011.
Patients with HCV-related decompensated cirrhosis should be referred for consideration of liver transplantation.
Interferons and Pegylated Interferons
The 2 most frequently used recombinant IFN preparations in clinical trials are IFN alfa-2b (Intron-A) and IFN alfa-2a (Roferon), which differ from each other by only a single amino acid residue. IFN alfacon-1 (Infergens), or consensus IFN, is a genetically engineered compound synthesized by combining the most common amino acid sequences from all 12 naturally occurring IFNs.
IFN alfacon-1 has greater cytokine-induction, antiviral, antiproliferative, natural killer cell, and gene-induction activities than both IFN alfa-2a and IFN alfa-2b on an equal-mass basis. However, initial studies of the recommended consensus IFN dose of 9 mcg in IFN-naive patients with chronic hepatitis C, such as that by Tong et al, have resulted in viral response rates similar to those of standard IFN-alfa monotherapy.
The addition of propylene glycol (PEG) molecules to IFN has led to the development of long-lasting IFNs that have better sustained absorption, a slower rate of clearance, and a longer half-life than unmodified IFN, which permits more convenient once-weekly dosing. The FDA has approved PEG-IFNs for the treatment of chronic hepatitis C.
Two PEG-IFN preparations are available. PEG-IFN alfa-2b (PEG-Intron) consists of IFN alfa-2b attached to a single 12-kd PEG chain; it is excreted by the kidneys. PEG-IFN alfa-2a (Pegasys) consists of IFN alfa-2a attached to a 40-kd branched PEG molecule; it is metabolized predominantly by the liver.
IFN monotherapy in acute hepatitis C
Although the short courses of standard IFN monotherapy introduced in the 1980s by Hoofnagle et al, Davis et al, and Di Bisceglie et al led to sustained improvement in liver disease and loss of virus in less than 10% of patients, these therapies were the first to cure chronic viral hepatitis. While combination therapy with IFN or PEG-IFN and ribavirin have become the standard of care for chronic disease, IFN monotherapy may play a role in the treatment of acute HCV infection.
Jaeckel et al reported that treatment with IFN alfa-2b prevented chronic infection in 98% of a group of 44 German patients with acute hepatitis C. In this study, patients received 5 million U/day of IFN alfa-2b subcutaneously for 4 weeks and then 3 times per week for another 20 weeks; the IFN alfa-2b was well tolerated in all patients but one. Because spontaneous resolution is common, no definitive timing of therapy can be recommended; however, waiting 2-4 months after the onset of illness seems reasonable.
PEG-IFN monotherapy
Several reports have documented improved SVR with PEG-IFN monotherapy. In a randomized study of patients with chronic hepatitis C, Zeuzem et al found that PEG-IFN alfa-2a at 180 mcg subcutaneously administered once per week was associated with a higher rate of virologic response than IFN alfa-2a at 6 million U subcutaneously administered 3 times per week for 12 weeks followed by 3 million U 3 times per week for 36 weeks. Findings were 69% versus 28% at week 48 of therapy and 39% versus 19% at week 72 of therapy.
In a controlled trial of persons with cirrhosis, Heathcote and colleagues reported an SVR rate of 30% after 48 weeks of therapy with PEG-IFN alfa-2a, compared with 8% for patients treated with standard IFN alfa. Adverse effects were not significantly higher with the pegylated product.
Interferons and Ribavirin
A major advance in the treatment of chronic hepatitis C was the addition of the oral nucleoside analogue ribavirin to the IFN regimen. As reported in the landmark 1998 studies by McHutchison et al and Poynard et al, IFN alfa-2b and ribavirin combination therapy for 6-12 months resulted in sustained eradication rates of 30-40%. However, patients with HCV genotype 1 who were treated for 12 months had a much less favorable response than patients infected with genotypes 2 and 3 who received a 6-month course of therapy.
PEG-IFN therapy with ribavirin
As with IFN alfa, the addition of ribavirin to PEG-IFN heralded a new era in the treatment of chronic HCV. The benefits of combination therapy were documented in 3 landmark trials: Manns et al from 2001, Fried et al from 2002, and Hadziyannis et al from 2004.
Manns et al reported a significantly higher SVR rate in patients given higher-dose PEG-IFN alfa-2b plus ribavirin than in patients given lower-dose PEG-IFN alfa-2b plus ribavirin or given IFN alfa-2b plus ribavirin. Adverse-effect profiles in the 3 treatment groups were similar. Secondary analyses identified body weight and HCV RNA viral load less than 1 million copies per milliliter as important predictors of SVR.
Adverse effects
Adverse effects are common with IFN and ribavirin combination therapy. Approximately 75% of patients experience one or more of adverse effects.
Adverse effects of IFN include the following:
- Hematologic complications (ie, neutropenia, thrombocytopenia)
- Neuropsychiatric complications (ie, memory and concentration disturbances, visual disturbances, headaches, depression, irritability)
- Flulike symptoms
- Metabolic complications (ie, hypothyroidism, hyperthyroidism, low-grade fever)
- Gastrointestinal complications (ie, nausea, vomiting, weight loss)
- Dermatologic complications (ie, alopecia)
- Pulmonary complications (ie, interstitial fibrosis)
Adverse effects of ribavirin include the following:
- Hematologic complications (ie, hemolytic anemia)
- Reproductive complications (ie, birth defects)
- Metabolic complications (ie, gout)
Because of the risk of reproductive complications from ribavirin, recommend that patients and their spouses not become pregnant while either is on therapy and for 6 months after the completion of treatment.
Protease Inhibitors
Despite the improved results achieved with the addition of ribavirin to PEG-IFN, the current available therapies for chronic HCV infection are effective in fewer than 50% of patients with HCV genotype 1. A new class of direct-acting antiviral agents (DAAs) has revolutionized the treatment of HCV genotype 1 infection. These drugs target specific enzymes involved in viral replication. The addition of these new protease inhibitors to pegylated interferon and ribavirin is becoming the new standard of care for the treatment of chronic HCV infection.
Boceprevir (Victrelis) and telaprevir (Incivek) are HCV NS3/4A protease inhibitors and were approved by the US Food and Drug Administration in May, 2011. Each is indicated for treatment of chronic HCV genotype 1 infection in combination with PEG-IFN alfa and ribavirin in adults with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.
Boceprevir was evaluated in 2 phase 3 clinical trials with nearly 1,500 participants. In both trials, two thirds of patients receiving boceprevir in combination with peginterferon alfa and ribavirin experienced a significantly increased sustained virologic response (ie, undetectable HCV RNA level) compared with those taking peginterferon alfa and ribavirin alone.
Hepatitis C and B Coinfection
Coinfection with HCV and hepatitis B virus (HBV), in the absence of HIV infection, is relatively uncommon in the United States, and optimal treatment regimens have not been established. However, 2 important studies are worth mentioning. Villa et al reported that 9 million U of standard IFN 3 times weekly for 3 months could clear HCV in 31% of patients with HCV-HBV coinfection.
AQUIRED IMMUNODEFICIENCY SYNDROME
(AIDS/HIV infection)
http://www.cdc.gov/globalAIDS/default.html
A secondary immunodeficiency syndrom caused by a virus and characterized by severe immune deficiency resulting in opportunistic infections, malignancies, and neurologic lesion in individuals without prior history of immulogic abnormality.
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History
In June 1981 the Morbidity and Mortality Weekly Report carried a report of five deaths due to overwhelming Pneumocystis carini pneumonia in
From early 1982 onwards, efforts to identify the causative agent intensified and in may 1983 group from the institute Pasteur, Paris, reported the isolation and propagation of a T-lymphotropic retrovirus, lymphoadenopathy associated virus, LAV from the lymph node of a patients with persistent lymphoadenopathy, a syndrome know to be assotiated with, and preceding the development of AIDS.
Etiology
Retroviruses are very small viruses composed of a single strong of RNA, the intermediate nucleic acid in the production of proteins (Fig. 1). Normally, the flow genetic information starts with a piece of DNA, which makes a piece of RNA, which in turn codes for, protein. Everything flows in that direction. Retroviruses contain a unique enzyme called reverse transcriptase, which allows this single strand of RNA, that is, the virus, to make itself back into a piece of DNA, going backward against the flow of genetic information. Hence, «retrovirus». This piece of viral DNA than inserts itself into the genetic material of the cell that it is infecting, in this case the helper T-lymphocytes, and it remains intertwined there for the life at the cell.
Fig.1. HIV retrovirus
The emergence of a new infections agent in a human population can have only a limited range of explanation; either the infection was previously in an isolated human population from which it had been exported though some societal change, or else it might have been a zoonosis newly exposed to human transmission. A third line of explanation, that of an extraterrestrial or even a man-made origin, has been popular with conspiracy theorists, but will not be furthers discussed. The natural history of HIV 1 infection is marked by the long period of time between infection and disease.
Epidemiology
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The major transmission routes of human immunodifficiency virus are sexual contact, parenteral exposure to blood and blood products and perinatal transmission. early in the AIDS epidemic, epidemiological studies establish that receptive rectal intercourse was the predominant mode of HIV-1 acquisition by homosexual man. Other practices that could traumatize the rectal mucosa appeared to increase further the infection risk for the receptive partner. Insertive rectal sex could also place a men at risk for HIV-1 infection, although the insertive partner would be at lower risk than the receptive partner.
On a world-wide basis sex between man and women apparently is the most common mode of acquiring HIV-1 infection heterosexual transmission accounts for the vast majority of cases. In other country where AIDS cases attributed to heterosexual transmission, although still a small percentage of the total number of reported cases comprise the most rapidly growing category. Therefore an understanding of the rate at which HIV-1 is transmitted between heterosexual couples and of the factors that may impede or enhance heterosexual transmission is important in slowing the worldwide HIV-1 epidemic.
In the country, where HIV-1 infection is more common in men than women, studies of female-to-male transmission of HIV-1 infection are both fewer and smaller than studies of male-to-female transmission. Available date suggest female-to-male transmission may be less efficient than male-to-female transmission.
Overall these American and European studies suggest that heterosexual transmission from HIV-infected persons to their regular sex partner is relatively inefficient, especially female-to-male transmission. Furthermore, the risk of heterosexual transmission is not related simply to the number of episodes of sex with HIV-infected person because some people have remained uninfected after hundreds of such contacts whereas others have become infected after a single episode of intercourse.
Infectivity may be higher during early infection before the development of antibodies to HIV-1, also genital ulcer diseases and inflammation of the genital tract lead to increased susceptibility to HIV infection.
Mother-to-infant transmission of HIV apparently is relatively efficient; without treatment approximately one in the four infants born to seropositive mothers is infected. With one rapid spread of infection to women of reproductive age perinatal transmission is now a major consequence of HIV epidemic. The precise rate of perinatal transmission in a given setting has been difficult to define because of problems in the infant and the difficulties in maintaining long-term follow-up. Uninfected children born to seropositive mothers may retain passively aquired maternal antibody for 6 to 18 months.
Extensive laboratory research and epidemiological studies indicate that HIV is not transmitted by shaking hands, hugging, kissing, contacting bodily secretion such as sweat, mucus (as in sneezing or coughing) or salive. Nor is HIV transmitted by food, swimming at a pools, drinking at a water fountain and also bloodsucking mosquitoes or other arthropods.
Pathogenesis
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Following infection across a genital surface, involving infection of CD-4/CCR 5 bearing cells in the mucosa or submucosa, the virus presumably migrates to a regional lymph node, where viral replications occurs. A number of rounds of viral replication than occur within the bounds of the regional lymph node as no detectable virus or immune respons occurs for up to 42 days post infection. When the quantity of infected cells exceeds a threshold, viremia occurs, and the symptoms of an acute non-specific viral illness with tende adenopathy, sore troath, diffuse macular rush, arthralgia and fever. Following the acute viremia, when up to 107 viral particles /ml plasma can be found, a primary immune response develops with antibodies to viral proteins and a cytotoxic T-cells response, which limit viral replication and clear viral particles from the plasma. The reduction the viral load in plasma is not matched by a clearance of provirus in peripheral blood mononuclear cells, and cellular viremia continues in the face persistent and sustained cellular and humoral immune response for the duration of the infection. Even while plasma viral load is suppressed by the immune response, CD-4 T-lymphocyte number foll in linear manner over time. The most plausible explanation for the pathogenesis of AIDS over time is the sustained less CD-4 cells by ongoing HIV viral replication iature peripheral blood T-cells and by a slight failure of production of match peripheral destruction of HIV CD-4 cells. However, recent controversy over the pathogenic mechanisms and homestasis of T-cells has revealed that simple viral cytopatphic effect on CD-4 cells may be overly simplistic model.
During the course of HIV infection, CD-4 cells continue to decline in peripheral blood and plasma viral load slowly rises. Over a definite period CD-4 cells number declines from a 800 to 200 ml; at this level, the probability of the cellular immune system containing latent or environmental infections such as P. carinii falls and clinical opportunist infection becomes increasingly possible. As the viral load rises. HIV isolates with altered co-receptor usage appear which can use the CXCR-4 chemocine receptor rather than CCR-5; these isolates are more cytopathic in vitro, and may lead to wider tissue distribution of HIV in later disease, AIDS is therefore, the clinical condition of an immune system which is sufficiently compromised by HIV infection that there is an inability to protect against the growth of low grade pathogenes or viral indeced tumors.
The fact that this virus, after infection of the host, besides destroyed strong immune system also can spread to many body tissues. The ultimate outcode of the infection depends on the host’s immune reaction to the virus either through suppression of HIV replicationor through killing of the infected cell. in some individuals an active immune system has prevented development of the disease for years. The factors important in maintaining this immune response are not yet know and merit close attention. The immune deficiency produced by HIV infection makes patients suseptible to infection by a variety of organisms, including viryses, bacteria, fungi and parasites that are of low pathogenecity in the normal individual and of variable prevalence in different part of the world. In some individuals the immune system appears to make enhancing antibodies to HIV and this phenomenon occurs particularly with progression of disease. It is related to change to antibodies made and in some cases to modifications in the virus so that is more sensitive to enhancing antibodies. Moreover, the immune system can hyperreact, with production of antibodies that might also hasten the development of disease. Clearly changes in the virus and the immune response of the host play important roles in the ultimate steps leading to AIDS.
Clinical manifestations
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The time from exposure to HIV until the onset of the acute clinical illness is typically 2 to 4 weeks, although longer incubation period have been reported. The clinical illness is acute in onset and lasts from 1 to 2 weeks. It can be associated with an appreciable degree of morbidity and patient may require hospitalization. The main clinical features of primary HIV infection reflected both the lymphocytopatic and neurologic tropism of HIV. Patients report fever, lethargy, fatigue, headaches, retro-orbital pain, sore throat, muscular pain, occasional diarrhea, maculopustular rash and the onset of swollen lymph nodes (swollen glands). Meningoencephalitis may also occur. Lethargy and malaise are frequent, often severe and may persist for several months after resolution of the other clinical manifestations of primary HIV infection. Lymphoadenopathy develops in approximately 70% of persons, generally in the second week of the illness and usually concomitant with the development of peripheral lymphocytosis, reflects the fact that HIV has activated B-lymphocytes to become plasma cells and secrete HIV antibodies.
Fig.2. AIDS lymphoadenopathy
The lymphoadenopathy may be generalized, but the occipital, axillary and cervical nodes are most commonly involved (Fig. 2). The lymph node enlargement persist after the acute illness bat tend to decrease with time. Splenomegaly has also been reported. The mechanism for this splenomegaly is not apparent; it may be related to increased clearance of virally infected lymphocytes. The most frequently reported dermatologic evidence of primary. HIV infection is an erythematous, nonpruritic maculopapular rash. This rash is generally simmetric, with lesions 5 to 10 mm in diameter, and affects the face or trunk, but it can also affect the extremities including the palms and soles, or can be generalized. Other skin lesions noted during primary HIV infection include a roseola-like rash, diffuse urticaria, vesicular, pustular exanthema and enanthema, desquamation of the palms and soles and alopecia. Mucocutaneous ulceration is a distinctive feature of primary HIV infection. Ulcer have been reported on the buceal mucosa, gingiva, or palate, esophagus, anus, and penis. They are generally round or oval and sharply demarcated, with surrounding mucosa that appears normal. The tongue of patient showing the characteristic symptoms of thrush. Note the milk-white flakes of C. albicans on the tongue surface. An unexplained incident of thrush is often considered an early sign that HIV infection is present. Patients also experience weight loss of as much as 10 % of baseline body weight or more. Constant low-grade fever and diarrhea extending over several weeks. In addition, the fatigue may be so overwhelming that patients cannot lift their heads from the pillow on waking in the morning. One of the most troublesome aspects is the night sweats. Individuals perspire so heavily at night that the bed linens and nightwear become drenched with sweat. Saturation can be extensive enough to require linen changes, and sleep is fitful at best. Few other microbial diseases are accompanied by such heavy sweating.
The isolation of HIV from cerebrospinal fluid (CSF) during primary HIV infection indicates that infection of the central nervous system (CNS) occurs soon after exposure. Elevated neopterin and β2-microglobulin levels have also been found in CSF during primary HIV infection both in individuals with and without clinical meningitis, suggesting that the cellular immune system in the CNS may be activated during this stage even without the development of overt neurologic symptoms or signs. The most commoeurologic symptoms are headaches, retro-orbital pain (particularly during eye movement) and photophobia. Several cases of aseptic meningoencephalitis during primary HIV infection have been reported.
Prolonged infection with HIV is often completely asymptomatic; however, a minority of patients complain of nonspecific constitutional symptoms in the month or years after primary infection. Patients commonly complain of being easily fatigued and report the need to reduce their normal activities somewhat. In patients with more advanced HIV disease and severe de pletion of CD4 cells, constitutional disease may primarily reflect immunosupression or may herald the onset of opportunistic infections or malignancies. Patients with progressive constitutional symptoms should be evaluated carefully for opportunistic pathogens. A history of respiratory, neurologic, gastrointestinal and dermatological symptoms should be elicited and a thorough physical examination completed.
In the late stages of HIV infection when immune defenses have been severely compromised and systemic complications have begun to accumulate, the nervous system becomes highly susceptible to a wide array of disorders involving all levels of the neuraxis, including meninges, brain, spinal cord, peripheral nerve, and muscle.
Systemic lymphoma complicating HIV infection may secondarily to the central nervous system involving the meninges, clinical manifestation may be cryptic but usually include cranial nerve palsies, head aches, or increased intracranial pressure.
From an early stage it become clear that the nervous system was frequently involved in HIV infected patients. Among the severe and life-threatening infections experienced by those with immune deficiency were brain abscesses due to toxoplasmsis. As other neurologic manifestations emerged without signs of recognizable opportunistic infection it became clear that HIV was probably directly neurotropic as well as lymphotropic.
Toxoplasma gondii is an obligate intracellular parasite for which the primary host is the cat. Humans may acquire it from the cat by the fecal-oral route. in man primary infection is usually asymptomatic unless congenitally acquired. The organism forms cysts in all tissues which persist for life and are the source of recrudescent infection in the compromised host. Infection in the brain is usually multifocal as old encysted parasites become actively pathogenic again. The clinical presentation may be focal or diffuse but is a cerebrovascular accident, but is more usually progressive aver a few days or a week or two.
Peripheral neuropathies of several types can complicate the various stages of HIV infection. Early in the course of HIV infection a Guillain-Barre type of neuropathy may be seen. The clinical picture is the same as the familiar acute inflammatory or postinfectious neuropathy, with weakness of limb and facial muscles, minor sensory symptoms and loss of tendon reflexes. The weakness tends to be both proximal and distal. There bay be backache and limb pains. There is evidence that the axonal neuropathy in the late stages of the disease correlated with the presence of dementia. Its ethnology is unknown, but it has been suggested that it may be a direct effect of HIV.
The most prevalent opportunistic disease among persons with HIV in late stage is Pneumocystis carinii pneumonia. Recently, however, studies of ribosomal RNA of P. carinii have shown that phylogenetically the organism is most closely related to the Ascomycetes (yeasts): thus P. carinii should probably be considered a fungus rather than a parasite. This reclassification has little clinical relevance but may suggest new therapeutic approaches and culture techniques. P. carinii is thought to have a life cycle consisting of three stages: cyst, whish are spherical or crescent-shaped form 5 to 8 mm in diameter; sporozoites or intracystic bodies, found only within the cyst; and tropozoites, found outside the cyst and believed intermediate between the sporozoite and the cyst. The Giemsa stain is taken up by both the intracystic sporozoites and extracystic tropozoites; cyst are not pozitively stained and cannot be seen except as negative images within the matrix of a clump of tropozoites. Infection with P. carinii is common early in the life and dose not generally results in symptomatic disease in immunocompetent hosts. Until the occurrence of the epidemic of infection with the HIV P. carinii pneumonia was an uncommon, sporadic disorders that occurred primary in patient with leukemia or other recognized causes of impairment of host defences and in patients who were given immunosuppressive therapy. Several studies in the United States have shown that circulating antibodies to P. carinii develop in mot children by age 2 to 3 years, leading to the conclusion that asymtomatic infection with P. carinii is nearly universal at least in the areas where these studies were conducted. Patients with P. carinii pneumonia usually have had non-specific symptoms such as fever, fatigue, and weight loss for weeks to months before developing respiratory symptoms and often have other HIV-related disorders that indicate severe immunosupression. The most common presenting symptoms of P. carinii pneumonia are fever, non-productive cough, and progressive shortness of breath. IN patient with P. carinii pneumonia chest radiographs most often show diffuse interstitial infiltration involving all portion of the lungs. Several variations may be seen. The infiltration may be heterogenously distributed throughout the lung, or it may be miliary in appearance. Diffuse or local air-space consolidation may also be noted. In patients who are being given aerosol pentamidine prophylaxis, focal upper lobe infiltration are relatively common. Cystic changes or pneumatoceles may occur, especially during the healing process, and cavitation withing pre-existing nodular lesions has been described. Probably as a result of the cystic or cavitary processes, spontaneous pneumothorax may occur. Pleural effusion and intrathoracic adenopathy are very uncommon with P. carinii pneumonia.
Since the beginning of the HIV epidemic an increasing association of Mucobacterium tuberculosis infection with HIV infection has beeoted. Between 1978 and 1985 the yearly rate of tuberculosis more than doubled at one
The association of disseminated Mycobacterium avium complex (MAC) infection with HIV was recognized early in the HIV epidemic. Disseminated MAC infection has been reported only rarely in patients without HIV. Disseminated MAC infection occurs exclusively in patients with very advanced HIV disease essentially only in patients with CD4 lymphocyte counts<100/ml. MAC is a ubiquitous soil and water saprophyte. The source of MAC invasion in HIV patients may be gastrointestinal or respiratory. The presence of large clusters of mycobacterium within macrophagas of the small bowell lamina propria suggests the bowel wight be the portal of entry. However, respiratory isolation of the MAC also frequently precedes disseminated infection, suggesting MAC infection may begin in the lungs as well. Since most HIV patients with disseminated MAC infection have other concomitant infections or neaplasms and since MAC appears to cause little histopathologic evidence of inflammatory response or tissue destruction, the relationship between constitutional symptoms, organ dysfunction, and MAC infection has been uncertain.
Four clinical syndromes often over lapping, have been associated with disseminated MAC infection.
– Systemic symptoms. Fever, malaise, weight loss often associated with anemia, neutropenia.
– Gastrointestinal symptoms.
– Chronic diarrhoea and abdominal pain (MAC infection of colon often observed at autopsy)
– Chronic malabsorbtion (histopatologic changes in small intestine similar to those with Whipple’s disease often observed at autopsy)
– Extrabiliary obstructive jaundice secondary to periportal lymphadenopathy.
Cryptococcus neaformans and tuberculosis are the major opportunistic infection complicating the HIV epidemic world-wide. Although other pathogens may dominate on individual continents or in specific regions, no other major pathogen poses as great a global threat to those immunocompromised by HIV infection. The high mortality and morbidity rates associated with cryptococcal infection and the toxicity of traditional therapy have sparred intense interest iew treatment alternatives. A better understanding of the natural history of HIV-mediated immunodepression has seen the emergence of debate about the use and advisability of fungal prophylactic. This organism a common resident of the lung, is often inhaled from the air. It grows actively in the droppings of pigeons and enters the air in wind borne particles. The fungus is generally noninfectious, but in patients with HIV it multiplies in the lungs, spreads to the blood and localized on the brain and its coverings. The clinical presentation of cryptococcal disease in HIV patient is often subtle and nonspecific. A prolonged febrile prodrome, indistinguishable from that accompanying other opportunistic infections is common. Frequently no localizing signs or symptoms are present to guide the physician toward the diagnosis of cryptococcal disease. Although the portal of entry for C. neoformans is the lung. Pulmonary cryptococcosis is usually clinically. Most cases of pulmonary cryptococcal infection are discovered serendipitously, not because of organ specific signs or symptoms. Occasionally, however, pulmonary symptoms dominate the clinical presentation and progression to respiratory failure and death are not unknown. However, among those HIV-infected patients with cryptococcal disease and without CHS involvement, fully two thirds had cough and shortness of breath. In contrast only 18% of those patients with culture-proven CNS disease had respiratory symptoms. These numbers add weight to the argument that all patients with CNS involvement have or have had antecedent pulmonary infection. Blood-borne spread to any organ, but the organism has a predilection for the CNS. It causes a granulomatous meningitis with or without clinically evident pulmonary or disseminated infection. In addition, there may be small cysts in the cerebral cortex. The clinical presentation is usually with headache, fever, and constitutional upset; neck stiffness, photophobia and focal neurologic signs are present.
Skin disease is an extremely common complication of HIV infection, affecting up to 90% of persons. Some of the skin conditions also are commonly seen in uninfected persons (e.g. seborrheic dermatitis) but are of increased severity in the HIV infected person. Other skin diseases are relatively unique to HIV infection (Kaposi’s sarcoma)(Fig. 3).
Fig.3. Elements of Kaposi’s sarcoma
The average HIV infected patient has at least two and often more different skin conditions simultaneously. It is useful to classify the cutaneous disorder seen with HIV disease as either infectious disorder, hypersensitivity disorders and drug reactions, or neoplasms.
Oral lesions (Fig. 4) have been recognized as prominent features of HIV infection since the beginning of the epidemic. Some of these changes are reflections of reduced immune function manifested as oral opportunistic conditions, which are often the earliest clinical features of HIV infection. Some, in the presence of known HIV infection are highly predictive of the ultimate development of the full syndrome, whereas others represent the oral features of AIDS itself.
Fig.4. Oral lesions in AIDS
They include oral infections in patients with primary immunodeficiency, leukemia, and diabetes, and those resulting from radiation therapy, cancer chemotherapy and bone marrow supression. In the prospective cohorts of HIV infected homosexual and bisexual men hairy leukoplakia pseudomembranous candidiasis are the most common oral lesions.
Fig.5. Oral Kaposi’s sarcoma in AIDS
Kaposi’s sarcoma (KS) in patients with AIDS produces oral lesions in many cases (Fig. 5).
The lesions occur as red or purple macules, papules, or nodules. Occasionally the lesions are the same color as the adjoining normal mucosa. Although frequently asymptomatic, pain may occur because of traumatic ulcerisation with inflammation and infection. Bulky lessions may be visible or may interfere with speech and mastication. Diagnosis involves biopsy. Lesions at the gingival margin frequently become inflamed and painful because of plaque accumulation.
From the outset of the HIV epidemic, clinicians everywhere noted a high prevalence of the gastrointestinal (GI) signs and symptoms. Some of these manifestation such as weight loss, dysphagia, anorexia, and diarrhoea are almost universally among patients with HIV. Early and complete invasive and noninvasive evulation of these patients should be undertaken with particular attention to treatable non-HIV-associated biliary tract disease. Hepatic parenchymal disease likewise is common in patient with HIV infection.
Cramping paraumbilical abdominal pain, weight loss (Fig. 6, 7) and large-volume diarrhea are common in patient with HIV disease.
Fig.6. Loss of weight in AIDS
Fig.7. Loss of weight in AIDS
The majority of HIV patients with these complaints has specific small bowel infection. Certainly routine colonic bacterial pathogens such us Salmonella, Shigella and Campylobacter, which may be persistent and mimic chronic inflammatory bowel disease, should be excluded by the adequate culture techniques. Likewise, routine and atypical parasitic infestation including that caused by Giardia lamblia, E. histolytica, Criptosporidium and I. belli must be excluded. Colonic diarrhea usually is associated with frequent small volume stools, left lower quadrant or suprapubic cramping, rectal urgency (tenesmus), and proctalgia and dyskenesia (painful defecation). On occasion a small amount of bright red blood may be noted. Once again, in the majority of these patient with diarrhea of colonic origin, specific bacterial and parasitic pathogens can and should be easily isolated by careful analysis of the stool. In addition some patient may have classic herpetic perianal ulceration which can be diagnosed by specific viral culture of swabs taken directly from the perianal area. CMV proctocolitis has been described as having sigmoidoscopic features suggestive of focal ishemic colitis that is submucosal hemorrhages and discrete shallow ulceration of distal colonic mucosa. Once again, obtaining specific biopsy specimens for histology and viral culture is indicated. Even in the absence of focal or diffuse colonic mucosal changes, biopsy specimens should be taken for histologic evaluation to look for the occasional patient with Cryptosporidium whose stools have beeegative for this organism.
On occasion, patients with HIV may suddenly develop ascites. Since some HIV-infected patient may have underlying cirrhosis (caused by either alcohol consumption or viral hepatitis), a sizeable percentage of them will have transudative ascites related to their chronic liver disease. Careful evaluation of the ascites fluid, including performing cytology, and acid-fast stains should be done early to exclude patients with malignancy and tuberculosis peritonitis.
Malignancies as a complication of immunodeficiency have been well described in the literature, being recognized long before the advent of the HIV epidemic. The incidence of both Kaposi’s sarcoma (KS) and non-Hodgkin’s lymphoma (NHL) are marked by increased in immunosuppressed allograft recipients. It is therefore not suprising that patients with HIV infection, who also have proformed defects in cell-mediated immunity also develop these two malignancies. KS once a rarely reported malignancy is the most commoeoplasm affecting HIV-infected individuals. IT is seen primarily in homosexual men and has only rarely been reported in intravenous drug users or other risk groups. The pathogenesis of KS and HIV-infected patients remain uncertain. The natural history of KS associated with HIV infection more closely resembles that observed in immunosuppressed allograft patients. The disease tends to progress with time and is associated with the appearance of larger and more numerous cutaneous lesions (Fig. 8).
Fig.8. Cutaneous lesions in AIDS
However, the course of the disease is unpredictable. A patient may have relatively few lesions that remain stable over time. New cutaneous lesions may not appear for many months but may be followed by a sudden and rapid increase in disease activity. Visceral involvement with KS is extremely common and can involve almost any visceral site. Careful endoscopic examination will reveal gastrointestinal sites of disease in most patient.
Cutaneous lesions may become painful and if large cutaneous surfaces are involved can restrict movement. Lymphatic obstruction is common and can result in severe edema, most commonly involving the extremities or the face. visceral spread of KS is rarely symptomatic, particularly when it involves the gastrointestinal tract. Careful examination of the skin and oral cavity at each clinic visit is the key to early diagnosis. Once lesions are identified, histologic confirmation should be obtained.
The non Hodgkin’s lymphomas are a heterogenous group of malignancies. Their biologic behavior ranges from indolent requiring no therapy, to aggressive malignancies with few long-term survivors. In the most commonly used classification system for the NHL, these malignancies are divided into three major categories: low grade, intermediate grade, and high grade, according to pathologic characteristics of involved lymph nodes and morphologic criteria of the lymphoma cells.
Infection with the HIV is associated with a wide spectrum of hematologic abnormalities. These abnormalities are found in all stages of HIV disease and involve the bone marrow, cellular elements of the peripheral blood and coagulation pathways. The cause of these abnormalities is multifactorial. A direct suppressive effect of HIV infection, ineffective hematopoiesis, infiltrative disease of the bone marrow, nutritional deficiencies, peripheral consumption secondary to splenomegaly or immune dysregulation, and drug effect all contribute to the variety of hematologic findings in these patients. Many of these abnormalities are clinically significant, whereas others are more of academic interest.
Peripheral cytopenias are common in HIV-infected individuals and are due to either decreased production in the bone marrow or accelerated destruction in the peripheral circulation. In general the cytopenias increase in frequency as HIV-disease progresses. Anemia is the most common hematologic abnormality noted in patients with HIV disease. The largest HIV infection affects the lymphocyte, neutrophil and macrophage monocyte cell lines. Despite the hyperhammahlobulinemia noted in these patient, they suffer complications from both defective cellular immunity and dysregulated humoral immunity. The hallmark of HIV infection is progressive depletion of the CD-4 lymphocytes. This decrement presumably occurs through direct viral invasion of these cells. Early in HIV infection an initial increase in the CD-4 population occurs before a decline in the number of CD-4 cells is noted. Granulocytopenia independent of drug use is noted in approximately 50% of patients with HIV. Drug-induced neuthropenia is in the HIV-infected individual. Medication used to treat infection such as P. carinii pneumonia, toxoplasmosis and cytomegalovirus retinitis or colitis cause neuthropenia. Similarly, ridovudine is implicated as a cause of neuthropenia, ofteecessitating dose reduction or cessation of therapy. As for the complication of neuthropenia, most documented infection involve gram-negative organisms. The most common platelet abnormality found in HIV-infected patients is thrombocytopenia have only minor submucosal bleeding. characterized by petechiae, echymoses and occasional epistaxis. Rare patients have gastrointestinal blood loss. Laboratory findings reveal that patients generally have isolated thrombocytopenia, which usually is not accompanied by anemia and leukopenia. Patients with HIV infection, including those being treated with antibodies for an AIDS-opportunistic infection and those being treated with cytotoxic chemotherapeutic agents for HIV-related malignancies, may also develop thrombocytopenia secondary to a therapeutic intervention. In these patients severe thrombocytopenia should be managed as it is in the non-HIV-infected individual. Medications causing thrombocytopenia should be discontinued and platelet transfusion should be administered when indicated.
Diagnostics
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The first test developed to detected HIV infection was isolation of the virus through tissue culture. Unfortunately although sensitive for viral isolation the tissue culture procedure is expensive, time consuming and labor intensive. As a result soon after the initial discovery of HIV several tests were developed using protein products of the newly discovered virus to detect antibodies produced by the infected host. The two antibodi tests used most commonly are the enzyme-linked immunosorbent assay (ELISA) and the western blot. In addition to being less expensive, faster and easier to perform than viral culture, the ELISA and the Western blot test do not require working with like virus and therefore are safer. Over the best some years several novel techniques have been developed. The radioimmunoprecipitation assay (RIPA) is a more time consuming, and labor intensive test the Western blot, yet it provides much finer resolution of the high-molecular-weight envelope proteins than the western blot test. The RIPA is considered more sensitive and specific than the Western blot test, however, the time, expense, and need for active cell lines and radioactive materials make the RIPA a poor choice for routine testing in commercial laboratories. Rather its use is best reserved for difficult-to-diagnose cases. Like the RIPA the indirect immunofluorescence assay (IFA) requires preparation of HIV antigens that are expressed on infected cells and are stained subsequently. Infected cells are placed on the glass slides in a fixed monolayer and are incubated with patient serum. Anti-HIV antibodies present within the serum bind to antigens expressed on the surface of cells, and these bound antibodies are then detected with anti-human antibody that has been labeled with fluorescein isothiocyanate an ultraviolet-activated dye compound. after appropriate processing, the slide is viewed under a fluorescent microscope and the number of cells the intensity of staining and the staining pattern are assessed. Polymerase chain reaction (PCR) technique, introduced in the late 1980s, represent a major advance in the diagnosis of many disorders, including HIV infection. This powerful technique can amplify DNA existing in very small quantities through a series of binary replicative cycles. The PCR procedure can also be applied to RNA.
The pool of human lymphocytes possesses specific glycoproteins of their surface that play an important role in the cells activity and function CD-4 positive lymphocytes are the primary target of HIV infection, and the CD-4 receptor is the primary binding site of HIV. Throughout the course of chronic HIV infection the number of CD-4 lymphocytes is depleted and the loss of these cells is associated with development of the characteristic opportunistic infection and malignancies of AIDS. Thus the measurement of CD-4 positive lymphocytes is one of the most impotent determinates for clinically staging the disease status of HIV infected patients. In uninfected controls normal values for the CD-4/CD-8 ratio are 2.0 to 1.0. Normal values for CD-4 counts are generally 500 to 1000 cells/ml3 in adults.
Treatment
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Basic therapy consists of indication of antiviral agents. Use preparations, that inhibit the return transcriptasa of the virus: Azydotymidin (АzТ), Didanosin (ddi), Zalcytobyn (ddc), Stavodin (d4T), Lamivudin , Abacavir (АВС), Nevirapapin (NVP).
Till now monotherapy AZT (Retrovir, Zidovudin) was used. The preparation are prescribed (P.O.) 0,2 gr. 3 times per day constantly or courses, duration is not less than 3 months. Treatment will be carried out under the control of the general analysis of a blood with 2 times per one month during the first 2 months and subsequently once per month. In a stage preAIDS (secondary diseases) AZT is necessary to indicate till disappearance of a clinical symptomatology. If the clinical picture is not better Zidovidin is indicated only for that patient in which blood concentration are less than 500 cells in 1 mkl. With such treatment it is possible to prolong patients life, the number of resistant viruses to a preparation however is marked. So, monotherapy AZT is recommended only for prophylaxis of infection of fetus from mother.
Among new means with other mechanism of action use a specific inhibitor of proteases Krixivan, which is effective concerning resistant to AZT populations of a virus 0,8 g every 8 h. Preparations of a choice may be Rotonavir, Nelfinavir, Sacvinar-SGC, Amprenavir.
Recently it is proved, that efficiency of treatment essentially can be increased using a combination of two or three antiviral preparations. Therefore monotherapy was changed for polytherapy. The most frequently combination of two inhibitors of virus return transcriptasa (stavudin + didanosin, stavudin + lamivudin, zidovudin+didanosin, zidovudin + lamivudin, zidovudin+abacavir) and one inhibitor of a protease is used. At patients with high risk of disease progress (viraemia over 1 000 000 copies / ml.), and also in urgent cases use the two inhibitors of proteases and 1 -2 inhibitors of virus return transcriptasa.
Efficiency of specific treatment is controlled by monitoring with following criteria: 1) level HIV RNA in plasma; 2) quantity of T-lymphocytes CD4; 3) a clinical condition of the patient; 4) morphology and biochemistry of a blood (for detection of undersirable effects of an organism). Level HIV RNA in plasma is researched after 4-8 and 12-16 weeks from the beginning of treatment and subsequently each 3-4 months. The major condition of successful antiretrovirus therapy is its usage during all life of the patient, however it is interfered by a high toxicity of preparations and the complications connected with them. Complete treatment of patients with AIDS remains an unsolved problem. Last combination is considered the most effective, but also it does not cure patients with AIDS.
It is not less important preventive treatment of secondary diseases at AIDS. Against pneumocystic pneumonias the basic agent is Bactrimum. For initial prophylaxis of this disease Bactrimum is indicated 1 tablet duaring 3 days each week. At occurrence of pneumonia daily reception of preparation is prescribed. In case of an intolerance of Bactrim it is possible to indicate Dapsone or Primachin in a combination with Clindamicin. At presence of herpetic infections indicate Acyclovir.
Against criptococus and other funguses use Amphotericinum, against bacteria – the appropriate antibiotic. At sarcoma Kaposhi freezing elements of an eruption by liquid nitrogen, irradiation, chemotherapy are indicated. The immunotherapy of AIDS is at developing stage.
Viral hepatitis
Diagnosis
Preliminary diagnosis of viral hepatitis is based on epidemiological anamnesis, finding of the development of the disease, clinical picture with account of peculiarities of the ways of the transmission, duration of incubation period, presence of prejaundice period, presence of typical subjective and objective signs with account of the patients age.
Diagnosis is confirmed by routine and specific laboratory tests. In routine blood test of the patients with viral hepatitis lymphocytosis is observed with moderately expressed course and in serious course of the disease – anemia and leucopenia. ESR is slightly decreased. In urine urobilin and bile pigments are observed. During climax period, particularly during medium serious and serious forms, there are no stercobilin in stool.
Increased content of general bilirubin, primarily on account of its direct fraction is observed in blood serum during all jaundice period. Ratio of direct and indirect fraction composes 3:1. In all patients already in pre-jaundice period of the disease, during all jaundice period and in the period of early reconvalescence increased activity of ALT, AST is observed, testifying about the presence of cytolytic processes in liver.
Specific antigens (HBsAg) and antibodies to antigens of all known at present time viruses of hepatitis are revealed in the blood of patients with help of these methods. Discovery of antibodies of class of IgM testifies about acute disease. Discovery of other classes of immunoglobulins antibodies testifies about lingering or chronic course of viral hepatitis or about earlier infectious process or about disease in the past.
Differential diagnosis
Differential diagnosis of viral hepatitis is necessary to perform with diseases like leptospirosis, yersiniosis, mononucleosis, malaria, mechanic and hemolytic jaundice, toxic hepatoses.
Leptospirosis is characterized by acute beginning of the disease, often with chill, continuation of fever during of climax of the disease and jaundice, pain in muscles, especially in calfs, hemorrhagic syndrome. In blood leucocytosis with neuthrophillosis and shift in the formula to the left, accelerated ESR are observed. Activity of ALT and AST is moderately raised or normal relation of direct and indirect bilirubin 1:1. In blood serum concentration of urea and residual nitrogen increases. Stool is colored. In urine erythrocytes, leukocytes, like wax cylinders are marked in large quantity. Diuresis decreased till anuria.
In generalized forms of yersiniosis jaundice may be also observed, however it is accompanied by fever, metastatic focuses in other organs and tissues, leucocytosis with nuetrophilosis, accelerated ESR, aggravations and relapses. Diagnosis is confirmed by serological methods with specific yersiniotic antigen.
In malaria there are clear alternation of attacks fever with chills, replaced by heat and sweat and periods of apyrexia. Often painful, increased in size spleen is marked. In blood hemolytic anemia, in fat drop blood and smear different forms of malarial plasmodia are reveled. In blood serum indirect fraction of bilirubin predominates.
In mechanic jaundice stones in gall bladder and bile passages, enlargement of head of pancreas and other signs are revealed with help of ultrasound investigation. In majority of the patients moderate increase of activity of ALT, AST, leukocytosis, accelerated ESR are marked. Hemolitic jaundice is characterized by anemia, accelerated ESR, increase of indirect fraction of bilirubin. Stercobilin is always present in stool.
Differential diagnosis of VH with hepatoses is complicated and demands from doctor thoughtful and painstaking work. During this essential significance possesses correctly taken anamnesis.
Outcomes of the disease
Viral hepatitis most often ends with complete reconvalescence. In some patients may be cholecystitis, cholangitis, pancreatitis, dyskinesia of bile excreting pathways after an acute hepatitis. In 5-10 % of patients lingering course with periodical aggravations, caused by prolonged persistence of virus is observed. In such cases chronic hepatitis develops. This variant of the course of the disease is typical of viral hepatitis B and C chronic hepatitis may end up by liver cirrhosis.
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Treatment
Treatment is used complex and depends on the clinical form and gravity of disease current. At mild current of a viral hepatitis in the acute period it is possible to prescribe only semi-bed regime, diet № 5, polyvitamines and desensitizing preparations: calcium gluconate, Diazolin, Diprazin or Tavegil. In case of meteorism, feeling of gravity in epigastrium area after the meal, unstable feces – Festal, Pancurmen, Allochol, Cholenzym are indicated.
At medioserious and serious current of the acute form of hepatitis a bed regime is provided together with the specific treatment. Desintoxication therapy consists of plentiful drink; 5 % solution of glucose, saline solutions, Ringer’s solution, Trisault, Quartasault, 20 % solution of Sorbit (or. Sorbitoli), donor Albumin (given in vein), one of enterosorbents SKN of different brands, carbaphosfer, Carbosilan, Sillard P, Enterosgel, Polyphepan. The quantity of drunk liquid should be balanced with a daily urine. Polarizing admixture: 3.7 gm potassium of Sody chlorid and 12 UN of insulin on 1 liter of 5 % solution of glucose was recommended. There are indicated the preparations improving metabolism in hepatocytes: Ascorbinic acid, Thiamin chlorid, Pyridoxine hydrochloride, cocarboxylase, Potassy Orotat, Riboxin, Citochrom C, Lipamid, Calcy Pangamat. Last two preparations are indicated mainly at accompanying hepatoses with fatty infiltration of liver (alcoholism, diabetes, thyrotoxicosis, an obesity etc.). For acidosis decreasing 2 % solution of sodium of a hydrocarbonate 25-50 mL (P.R.) 3-4 times per day or on 150-200 mL (I.V.) should be infused.
Among etiotropic agents moderate medical effect at acute virus hepatitis has human recombinative α-2-interferon – Reaferone, Intron A, Realdironi or analogue Laferone in powder, in amp. 1 000 000 IUN: from 1-st to 5-10-th day of the icteric period. Next days their efficiency falls. At acute hepatitis B Laferon is infused 1 000 000 IUN 2 times per day during 5-6 days, then 1 000 000 IUN 1 time per day during 5 days. If medical effect is insufficient, there should be continued infusing 1 million UN 2 times per week during 2 weeks. It is worthy to use Leicinferone as the basic component which is the admixture of natural α-interferons of donor leucocytes, the factor of necrosis of tumours and Interleicin-1. However many clinicians challenge expediency of indication of interferon at the hepatitis of acute period. More physiologic is the stimulation of endogenic interferonogenesis with the help of such inductores, as Mefanam acid, Prodigiosan, Pyrogenal, Nifluril, Cycloferon.
At threat of hepatonecrosis – glucocorticoids 150-200 mg are prescribed. The dose of prednisolon per day, must be reduced after the patient gets out of extremely serious condition. The volume of infusion solutions is enlarged up to 30-50 mL/kg per day. Ornithin (ornicetyl) promotes a linkage and removing out of organism nitrous bonds and improves a metabolism.
A lactulose reduces an adsorption of ammonia from intestine in blood, especially in combination with Neomycin. With the aim of oppression of processes of an autolysis there should be used inhibitors of proteolytic enzymes Contrical or Gordox each 8 hours (I.V.) intravenous dropping, at improvement of a condition synthetic inhibitors. At retention of liquid in organism it is required to use Spironolacton (Veroshpiron), Kaliumsaving diuretics, or saluretics-Furosemid, Etacrinic acid. Psychomotor exaltation is stopped by Sody hydroxybutyrate in combination with Sibazon (Seduxen), Haloperidol. At increasing of hepatic failure there are used antilymphocytic gamaglobulin during 1-5 days with the control of quantity of lymphocytes in a pereferic blood, apparatus methods of clearing of patients blood, hyperbaric oxygenation.
At cholestatic form of a virus hepatitis the are effective preparations which form complexes inside intestine with cholic acids which caot be soaked up, cholestiramin and Bilignin. Fenobarbital is used which is the inductor of synthesis of Glucouroniltransferas. This enzym is necessary for conjugation of bilirubin with glucuronic acid, and stimulating its egestion with bile. Fenobarbital is indicated with combination of Cyanocobalamin. Simultaneously for intensifying secretion of bile Nospan and Cholenzym are indicated. After the termination of an acholia duodenal tubages 5-10 % solution of magnesy sulfat (1/4-1/2 glasses), Sorbit or Xilit (20 gr on 100 mL of hot water) 1 hour before breakfast are applied.
Bioflavonoids – Convaflavin, Carsili, Legalone, Silibor, Quercetin are indicated in case of the alonged reconvalescence. At hyperaminotransferasaemia – Aevit or Tocopherol acetas, Thymalin, T-activin, Dipiridamol (Curantyl), Isoprinosin (has also antiviral property) – give positive effects. There are used also Saparal, Methyluracil (or. Methacil), Natry nucleinic, Thymalin in a combination with Dipiridamol, Hofitol.
Cholagogue agents – broths of flowers of immortele, hips, thyme, mints peppery at the rate of 1 dining spoon of a herb or a mixture to 1 glass of water are indicated for convalescents Fenobarbital with Cyanocobalamin are applied during 10 days in case of hyperbilirubinemia with prevalence of untied fraction of pigment; preparations of choice can be Cordiamin or Sibazone (Seduxen) which also stimulate glucoruniltransferase of hepatocytes. At hyperbilirubinemia mainly at the expence of connected fraction stimulate a bile secretion using oxygen cocktails with cholagogue herbs and honey. Vitohepat or Cobamamid stimulate neogenesis and hemopoes, accelerate regenerative processes in liver, course of treatment lasts 15-20 days. At astenia and hypoproteinemia, and also for elimination of catabolitic influences of glucocorticoids which were used at the acute period, anabolic hormones: such as methandrostenolon (Nerobol), Phenobolin (Nerobolil) or Retabolil are indicated. For elimination of the asthenic phenomena, there are used Novopasit, tinctura of Valeriana root (20 gm: 200 mL), herbs of neetle, Thyme, Bromidums, and in rather serious cases – Chlozepid (or. Eleny), Sibazon (or. Seduxen), Relany, Barbiturates.
At the dyspeptic phenomena caused by oppression of secretory function of digestion organs, also Allochol, Liobily, Cholenzym, Festal, Panzynorm forte, Pancurmen, Pancreatin, Pancitratit, Vobensym are widely used.
At posthepatitic hepatomegalias without signs of cytolisis it is not reasonable to indicate Lydase – promoting a resorption of a fibrous tissue, 10 injections every 2-nd day. It can be infused only after exception of inflammatory process in hepatobiliar ways (will carry out control duodenal intubation).
Chemotherapeutic preparations are indicated in case of the bacterial cholecystitis. At mild current of disease it is possible to use only a fortnight course of Nicodin, at appreciable changes antibiotics or Nitrofurans preparations are indicated.
It is possible to make antibioticosensetivity of microorganisms allocated from bile. For definition there are used mediums, which content bile of the patient as it influences on essentially activity of antibiotics. Use Ampicillin, Carbenicilin Dinatry salt, Erythromicin, Cefazolin, Furazolidone, Furagin, at Candida infection sody salt of Levorin. Chemiopreparations indicate in average therapeutic doses during 7 – 8 days.
Specific therapy of chronic virus hepatitises is carried out by preparations of α-interferon (Intron A, Roferon, Realdiron, Reaferon, Laferon). They are effective in case of low replicative activity of the virus determined in blood virus DNA (HBeAg) at a hepatitis B and virus RNA at hepatitis C. The additional indication is high activity of serum Alanineaminotransferase. One of the specified preparations inject (I.M.) or subcuteneous 3 – 5 million IUN per day 3 times per week during 6 months. Treatment should be stopped, if positive results were not observed after 3 months. The positive effect is observed at 40-50 % of patients with hepatit B and at 20-30 % of patients with hepatit C. At chronic hepatit D less than 10 % of patients are released from viruses even if treatment lasts 1 year. In some cases the success of immunotherapy of virus hepatitises may be increased if preliminary indicate short course of treatment about 6 weeks of glucocorticoids. Combined usage of interferon and Thymalin, Essentiale, Lamivudin, Chenodesoxycholyc acids has been proved.
The side-effects of α-interferon are noticed at half patients right after injection, among them are headache, fever, myalgia, arthralgia, general delicacy. They can be prevented by means of analgetics. Among the remote side-effects are: nausea, diarrhea, depression, irritability, leuco- and thrombocytopenia. Decreasing of a dose of preparation allows to weak these disorders. There are serious complications (sepsis, psychosis, autoimmune diseases), that demand an immediate cancellation of interferonotherapy.
At chronic hepatitis B in a phase of replication there are applied a peroral preparation Lamivudin (Zeffix). It provides the same level of seroconversion, as standard course of treatment by interferon.
At chronic hepatitis with low replicative activity of a virus preference is given to pathogenetic agents improving metabolic and reparative processes in liver, such as: Silibor, Carsil, Liv-52, Hepatofalk, Planta, Hepabenne, Antral, Tocopherol Acetat etc.
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Prophylaxis
If the patient is hospitalized, he should be placed in a private room with separate toilet facilities. The major reason for such isolation is to prevent the spread of type A hepatitis. Even with lax precautions, such spread is very rare; most patients with type A hepatitis are no longer excreting virus once they have become symptomatic. Nevertheless, there are exceptions, and isolation is prudent. Secretions and blood products should be handled with care gowns, masks, and gloves are not necessary, but a prominent sign reading “needle and blood precautions” is appropriate. Labeling of blood specimens from a patient with hepatitis, is a common practice. It should be stressed, however, that all blood from any patient should be handled as if potentially infectious.
If the patient with viral hepatitis is at home, the patient should be advised about care in personal hygiene – careful hand washing. Attention also should be paid to blood and blood products and the handling of cuts and lacerations.
Recommendations regarding the prevention of acute hepatitis are governed by the type of viral hepatitis that is being considered. In the case of acute type A hepatitis, all family members, and close personal contacts should receive immune serum globulin (ISG) at a dosage of 2-5 mL in as soon as possible after exposure. Office, factory, and school contacts do not need to be treated. Immune serum globulin can be given for up to 4 weeks after exposure, but it probably is only effective if given within 7-14 days.
In the case of acute type В hepatitis, prophylaxis only needs to be provided for “regular” sexual contacts. The best form of protection is argued Hepatitis В immune globulin (HBIG) at a dosage of 5 mL in as soon as possible and again 1 month later has been the conventional recommendation in this situation. However, the efficacy of HBIG in preventing the sexual spread of acute type В hepatitis has not been well proved. In addition, there is now evidence that postexposure immunization with HBV vaccine, can attentuate or prevent acute type В hepatitis. Vaccine should be given as soon as possible and then 1 month and 6 months later.
