Features of diagnosis and treatment of chronic viral hepatitis (B, C)

Diagnosis and treatment of chronic hepatitis. Differential diagnosis of infectious diseases, accompanied by jaundice (viral hepatitis, leptospirosis, tropical malaria, sepsis, yersiniosis, infectious mononucleosis), parasitic and helmints liver lesions and noninfectious jaundices (remedies, toxic hepatitis, alcoholic liver disease, unalcogol steatohepatitis , cholestatic jaundice, extraliver jaundices

Viral Hepatitis

 

The term hepatitis describes inflammation of the liver. Hepatitis may be caused by alcohol, drugs, autoimmune diseases, metabolic diseases, and viruses. Viral infection accounts for more than 50% of the cases of acute hepatitis in the United States.

The term viral hepatitis is often thought to be synonymous with diseases caused by the known hepatotropic viruses, including hepatitis viruses A (HAV), B (HBV), C (HCV), D (HDV), and E (HEV). However, the term hepatotropic is itself a misnomer. Infections with hepatitis viruses, especially hepatitis viruses B and C, have been associated with a wide variety of extrahepatic manifestations. Infrequent causes of viral hepatitis include adenovirus, cytomegalovirus, Epstein-Barr virus, and, rarely, herpes simplex virus infection. Newly discovered pathogens (eg, virus SEN-V) may account for additional cases of non-A/non-E hepatitis.
Also, see eMedicine’s patient education articles Hepatitis B; Hepatitis C; Cirrhosis;

Epidemiology of viral hepatitis

HAV; HBV; HCV; HDV, which requires coexisting HBV infection; and HEV cause 95% of cases of acute viral hepatitis observed in the United States. Whether hepatitis G virus (HGV) is pathogenic in humans remains unclear. HAV is the most common cause of acute hepatitis in the United States; HCV is the most common cause of chronic hepatitis. Typical patterns of virus transmission are as follows, with + symbols indicating the frequency of transmission (more + symbols indicated increased frequency):

Natural history of acute viral hepatitis

The term viral hepatitis can describe either a clinical illness or the histologic findings associated with the disease. Acute infection with a hepatitis virus may result in conditions ranging from subclinical disease to self-limited symptomatic disease to fulminant hepatic failure. Adults with acute hepatitis A or B disease are usually symptomatic. Persons with acute hepatitis C disease may be either symptomatic or asymptomatic (ie, subclinical).

Liver biopsy specimen showing ground-glass appearance of hepatocytes in a patient with hepatitis B

Typical symptoms of acute hepatitis are fatigue, anorexia, nausea, and vomiting. Very high aminotransferase values (>1000 U/L) and hyperbilirubinemia are often observed. Severe cases of acute hepatitis may progress rapidly to acute liver failure, marked by poor hepatic synthetic function. This is often defined as a prothrombin time (PTT) of 16 seconds or an international normalized ratio (INR) of 1.5 in the absence of previous liver disease.

Fulminant hepatic failure is defined as acute liver failure that is complicated by hepatic encephalopathy. In contrast to the encephalopathy associated with cirrhosis, the encephalopathy of fulminant hepatic failure is attributed to increased permeability of the blood-brain barrier and to impaired osmoregulation in the brain, which leads to brain-cell swelling. The resulting brain edema is a potentially fatal complication of fulminant hepatic failure.

Fulminant hepatic failure may occur in as many as 1% of cases of acute hepatitis due to hepatitis A or B. Hepatitis E is a common cause in Asia. Whether hepatitis C is a cause remains controversial. Although fulminant hepatic failure may resolve, more than one half of all cases result in death unless liver transplantation is performed in time.

Providing that acute viral hepatitis does not progress to fulminant hepatic failure, many cases resolve over a period of days, weeks, or months. Alternatively, acute viral hepatitis may evolve into chronic hepatitis. Hepatitis A and hepatitis E never progress to chronic hepatitis, either clinically or histologically.

Natural history of chronic viral hepatitis

Approximately 90-95% of cases of acute hepatitis B in neonates, 5% of cases of acute hepatitis B in adults, and as many as 85% of cases of acute hepatitis C demonstrate histologic evolution to chronic hepatitis. Some patients with chronic hepatitis remain asymptomatic for their entire lives. Other patients report fatigue (ranging from mild to severe) and dyspepsia.

Approximately 20% of patients with chronic hepatitis B or hepatitis C eventually develop cirrhosis, as marked by the histologic changes of severe fibrosis and nodular regeneration. Although some patients with cirrhosis are asymptomatic, others develop life-threatening complications. The clinical illnesses of chronic hepatitis and cirrhosis may take months, years, or decades to evolve.

 

Liver biopsy with hematoxylin stain showing stage 4 fibrosis (ie, cirrhosis) in a patient with hepatitis B

Chronic hepatitis B

Of HBsAg carriers, 10-30% develop chronic hepatitis. These patients are often symptomatic. Fatigue is the most common symptom of chronic HBV infection. Patients may occasionally experience an acute flare of their disease, with symptoms and signs similar to those of acute hepatitis. Patients also may have extrahepatic manifestations of their disease, including polyarteritis nodosa, cryoglobulinemia, and glomerulonephritis.

Chronic hepatitis B patients have abnormal liver chemistry results, blood test evidence for active HBV replication, and inflammatory or fibrotic activity on liver biopsy specimens (see the image below).

 

Liver biopsy with trichrome stain showing stage 3 fibrosis in a patient with hepatitis B

Patients with chronic hepatitis may be considered either HBeAg-positive or HBeAg-negative. See Diagnosis of acute self-limited HBV infection, below.

Ultimately, approximately 20% of HBsAg carriers (approximately 1% of all adult patients infected acutely with HBV) go on to develop cirrhosis or HCC (see the following image). See HBV and HCC, below, for recommendations regarding screening.

Patients with HBeAg-positive chronic hepatitis have signs of active viral replication with an HBV DNA level greater than 2 x 10⁴ IU/mL. HBV DNA levels may be as high as 10¹¹ IU/mL.

Patients with HBeAg-negative chronic hepatitis were presumably infected with wild-type virus at some point. Over time, they acquired a mutation in either the precore or the core promoter region of the viral genome. In such patients with a precore mutant state, HBV continues to replicate but HBeAg is not produced. Patients with a core mutant state appear to have downregulated HBeAg production. The vast majority of patients with HBeAg-negative chronic hepatitis B have a serum HBV DNA greater than 2000 IU/mL. Typically, HBeAg-negative patients have lower HBV DNA levels than do HBeAg-positive patients. Commonly, the HBV DNA is no higher than 2 x 10⁴ IU/mL.

In North America and Northern Europe, about 80% of chronic hepatitis B cases are HBeAg positive and 20% are HBeAg negative. In Mediterranean countries and in some parts of Asia, 30-50% of cases are HBeAg positive and 50-80% are HBeAg negative.

HBV and HCC

The incidence of HCC parallels the incidence of HBV infection in various countries around the world. Worldwide, up to 1 million cases of HCC are diagnosed each year. Most appear to be related to HBV infection. In HBV-induced cirrhosis, as in cirrhosis due to other etiologies, hepatic inflammation and regeneration appear to stimulate mutational events and carcinogenesis. However, in HBV infection, in contrast to other liver diseases, the presence of cirrhosis is not a prerequisite for the development of HCC. The integration of HBV into the hepatocyte genome may lead to the activation of oncogenes or the inhibition of tumor suppressor genes. As an example, mutations or deletions of the p53 and RB tumor suppressor genes are seen in many cases of HCC.

Multiple studies have demonstrated an association between elevated serum HBV DNA levels and patients’ increased risk for developing HCC. Conversely, successful suppression of HBV infection by antiviral therapy can decrease patients’ risk for developing HCC.

HCC is a treatable and potentially curable disease, whether the treatment entails tumor ablation (eg, with percutaneous injection of ethanol into the tumor), liver resection, or liver transplantation. The American Association for the Study of Liver Diseases recommends screening for HBV-infected individuals who are at high risk for HCC, including men older than 45 years, persons with HBV-induced cirrhosis, and persons with a family history of HCC.

Hepatic carcinoma, primary. Large multifocal hepatocellular carcinoma (HCC) in an 80-year-old man without cirrhosis

Ultrasonography of the liver and alpha-fetoprotein (AFP) testing every 6 months is recommended for these patients. No specific recommendations have been made for patients at low risk for HCC. Some authors recommend that patients at low risk (including inactive carriers) undergo AFP testing and liver chemistry testing, only, every 6 months. The author’s practice is to screen all patients with chronic hepatitis B with ultrasonography of the liver and AFP testing every 6 months; inactive carriers undergo liver chemistry testing and AFP testing every 6months. However, this is controversial.

Diagnosis of acute self-limited HBV infection

HBsAg is the first serum marker seen in persons with acute infection. It represents the presence of HBV virions (Dane particles) in the blood. HBeAg, a marker of viral replication, is also present. When viral replication slows, HBeAg disappears and anti-HBe is detected. Anti-HBe may persist for years.

The first antibody to appear is anti-HBc (HBcAb). Initially, it is of the IgM class. Indeed, the presence of IgM anti-HBc is diagnostic for acute HBV infection.

Weeks later, IgM anti-HBc disappears and IgG anti-HBc is detected. Anti-HBc may be present for life. The anti-HBc (total) assay detects both IgM and IgG antibodies. The presence of anti-HBc (total) demonstrates that the patient has had a history of infection with HBV at some point in the past.

In patients who clear the HBV, HBsAg usually disappears 4-6 months after infection, as titers of anti-HBs (HBsAb) become detectable. Anti-HBs is believed to be a neutralizing antibody, offering immunity to subsequent exposures to HBV. Anti-HBs may persist for the life of the patient.

Knowing key points helps in the interpretation of serology findings in acute HBV infection. The presence of HBsAg does not indicate whether the infection is acute or chronic. The presence of anti-HBc (IgM) is the sine qua non of acute HBV infection. The presence of anti-HBc (total) indicates that a patient has been infected with HBV at some point. The anti-HBc (total) remains positive both in patients who clear the virus and in patients with persistent infection.

The presence of anti-HBc (total) with a negative HBsAg and a negative anti-HBs indicates 1 of 4 things. First, the test result is a false positive. Second, the patient is in a window of acute hepatitis, between the elimination of HBsAg and the appearance of anti-HBs. This scenario is not observed in patients with chronic HBV infection. Third, the patient has cleared the HBV virus but has lost anti-HBs over the years. Fourth, the patient is one of the uncommon individuals with active HBV replication who is negative for HBsAg. This situation is diagnosed when either a positive HBeAg or a positive HBV DNA result is found. In the author’s opinion, the discovery of a lone positive anti-HBc (total) finding in the setting of negative HBsAg and negative anti-HBs findings mandates the performance of an HBV DNA assay by polymerase chain reaction (PCR).

Diagnosis of chronic HBV infection

HBsAg may remain detectable for life in many patients. Individuals who have positive findings for HBsAg are termed carriers of HBV. They may be inactive carriers or they may have chronic hepatitis. Anti-HBc is present in all patients with chronic HBV infections. HBeAg and HBV DNA may or may not be present. They reflect a state of active viral replication. HBV DNA levels are typically low or absent in inactive carriers. HBV DNA levels are higher in patients with chronic hepatitis B. High HBV DNA levels are associated with increased infectivity. Anti-HBs are usually absent in patients with chronic infection. If anti-HBs are present in a patient who has positive HBsAg findings, it reflects the presence of a low level of antibody that was unsuccessful at inducing viral clearance.

The following table summarize diagnostic tests for HBV.

Test	CHB HBeAg Positive	CHB HBeAg Negative	Inactive Carrier
HBsAg	+	+	+
anti-HBs	–	–	–
HBeAg	+	–	–
anti-HBe	–	+	+
anti-HBc	+	+	+
IgM anti-HBc	–	–	–
HBV DNA	>2 x 104 IU/mL (>105 copies/mL)	>2 x 103 IU/mL (>104 copies/mL)	<2 x 103 IU/mL (<104 copies/mL)
ALT level	Elevated	Elevated	Normal
ALT = alanine aminotransferase. Increasingly, experts in the field have used the nomenclature of IU/mL, as opposed to copies/mL.
Test	CHB HBeAg Positive	CHB HBeAg Negative	Inactive Carrier
HBsAg	+	+	+
anti-HBs	–	–	–
HBeAg	+	–	–
anti-HBe	–	+	+
anti-HBc	+	+	+
IgM anti-HBc	–	–	–
HBV DNA	>2 x 104 IU/mL (>105 copies/mL)	>2 x 103 IU/mL (>104 copies/mL)	<2 x 103 IU/mL (<104 copies/mL)
ALT level	Elevated	Elevated	Normal
ALT = alanine aminotransferase. Increasingly, experts in the field have used the nomenclature of IU/mL, as opposed to copies/mL.

The HBV vaccine delivers recombinant HBsAg to the patient, without HBV DNA or other HBV-associated proteins. More than 90% of recipients develop protective anti-HBs. Vaccine recipients are not positive for anti-HBc unless they were previously infected with HBV.

Pathologic findings of HBV infection

Inactive carriers of HBV have no or minimal histologic abnormalities detected on liver biopsy specimens.

Patients with chronic hepatitis B may have a number of classic histologic abnormalities. Inflammatory infiltrates composed of mononuclear cells may either remain contained within the portal areas or disrupt the limiting plates of portal tracts, expanding into the liver lobule (interface hepatitis). Periportal fibrosis or bridging necrosis (between portal tracts) may be present. The presence of bridging necrosis places the patient at increased risk for progression to cirrhosis. Ground-glass cells may be seen (see the first image below). This term describes the granular homogeneous eosinophilic staining of cytoplasm caused by the presence of HBsAg. Sanded nuclei reflect the presence of an overload of HBcAg. Special immunohistochemical stains may help detect HBsAg and HBcAg.

Liver biopsy specimen showing ground-glass appearance of hepatocytes in a patient with hepatitis B.

Treatment of chronic hepatitis B

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1079522/

In an ideal world, the treatment of patients with chronic hepatitis B would routinely achieve the loss of HBsAg. Indeed, the loss of HBsAg is associated with a decreased incidence of HCC and a decreased incidence of liver-related death in patients with HBV-induced cirrhosis.14 However, loss of HBsAg is only achieved infrequently in patients with chronic hepatitis B: in 3-7% of patients undergoing treatment with pegylated interferon (PEG-IFN)15,16,17 and in 0-5% of patients undergoing treatment with oral nucleoside or nucleotide agents.18

At this time, the key goal of antiviral treatment of HBV is the inhibition of viral replication. This is marked by the loss of HBeAg (in patients with HBeAg-positive chronic hepatitis B) and by the suppression of HBV DNA levels. Secondary aims are to reduce symptoms, if any, and prevent or delay the progression of chronic hepatitis to cirrhosis or HCC.

The agents currently in use for the treatment of hepatitis B include PEG-IFN-alfa 2a and the oral nucleoside or nucleotide analogues. Typically, PEG-IFN treatment is continued for 48 weeks for both HBeAg-positive and HBeAg-negative chronic hepatitis. The oral agents may be used for as little as 1-2 years. However, the majority of HBeAg-positive chronic hepatitis patients and almost all HBeAg-negative chronic hepatitis patients require indefinite therapy with the oral agents. Withdrawal of oral nucleoside/nucleotide analogue therapy in these individuals usually results in virologic relapse.

Candidates for antiviral therapy must have evidence of active HBV infection. At present, the typical threshold for treatment is a viral load of 2 X 104 IU/mL or more for patients with HBeAg-positive chronic hepatitis, 2 X 103 IU/mL or more for patients with HBeAg-negative chronic hepatitis, and 200 IU/mL or more for patients with decompensated cirrhosis.19

Patients with chronic hepatitis tend to have abnormal liver chemistry findings. Treatment may be offered to patients with a normal ALT level, but it may be less efficacious. Although performing a liver biopsy is not mandatory before treatment, the author recommends it. Liver biopsy is helpful for confirming the clinical diagnosis of chronic hepatitis B and for documenting the severity of liver disease. Detailed treatment recommendations have been published.5 Another resource is the practice guidelines of the American Association for the Study of Liver Diseases.7

Interferon-alfa and pegylated interferon alfa-2a for chronic hepatitis B

Interferons have both antiviral and immunomodulatory effects. Treatment with IFN-alfa is appropriate for some patients with chronic hepatitis B.

In th 1990s, the most commonly used interferon was IFN-alfa-2b. The medication was dosed at 5 million U given subcutaneously (SC) every day for at least 16 weeks or 10 million U given subcutaneously 3 times per week for at least 16 weeks. An elevation in the ALT level was common 8-12 weeks after the start of therapy. This change may have represented interferon-induced activation of the cell-mediated immune system.

Data have demonstrated the increased effectiveness of PEG-IFN-alfa-2a compared with the nonpegylated IFN-alfa.20 In one study of HBeAg-positive chronic hepatitis B, patients received a 48-week course of PEG-IFN-alfa-2a 180 mcg given subcutaneously once weekly.16 Seroconversion from HBeAg positivity to HBeAb positivity was seen in 32% of patients. A reduction of the serum HBV DNA from a mean of 1010 copies/mL to <105 copies/mL was seen in 32% of patients. ALT levels normalized in 41% of patients. Liver histology also improved in treated patients.

In HBeAg-negative chronic hepatitis B, a 48-week course of PEG-IFN-alfa-2a 180 mcg given subcutaneously once weekly also produced promising results.17 A reduction of the serum HBV DNA from a mean of 107 to <20,000 copies/mL was seen in 43% of patients. HBV DNA levels were reduced to <400 copies/mL in 19% of patients. ALT values normalized in 59% of patients. Liver histology improved in a significant number of patients. However, enthusiasm about using PEG-IFN-alfa-2a in HBeAg-negative patients is tempered by the relatively high rate of virologic relapse that occurs.

Patients with HBV genotypes A and B appear to be good candidates for treatment with PEG-IFN-alfa-2a. The drug might also be considered in young patients with a relatively brief history of HBV infection, ALT >100 U/L, and a relatively low serum HBV DNA level. Interferon is less effective in patients with (1) lifelong HBV infection, (2) an ALT level <100 U/L, (3) a high HBV DNA level, (4) end-stage renal disease (ESRD), (5) HIV infection, or (6) a need for immunosuppressive therapy (eg, after organ transplantation).

Adverse effects of interferon are common and lead to discontinuation in about 5-10% of patients. Adverse effects include flulike symptoms (eg, fatigue, fever, headache, myalgia, arthralgia), neuropsychiatric symptoms (eg, depression, irritability, somnolence), hematologic effects (eg, granulocytopenia, thrombocytopenia), and other miscellaneous effects (eg, pain at injection site, dyspepsia, alopecia, thyroid function abnormalities).

The relative lack of side effects of the oral nucleoside and nucleotide analogues and their high rate of achieving undetectable HBV DNA levels have made them attractive as potential first-line agents for HBV infection. However, treatment with PEG-IFN-alfa-2a offers the hope of a finite course of treatment and the potential for achievement of HBsAg negativity. This contrasts with the oral agents, which are frequently prescribed indefinitely and infrequently produce HBsAg negativity.

Lamivudine for chronic hepatitis B

Lamivudine (Epivir; GlaxoSmithKline) is the negative enantiomer of 2’3′-dideoxy-3′-thiacytidine. This synthetic nucleoside analogue inhibits DNA polymerase–associated reverse transcriptase and can suppress HBV replication.

In patients with HBeAg-positive chronic hepatitis, lamivudine 100 mg/d orally for 1 year resulted in HBeAg seroconversion in about 20% of patients and achieved HBV DNA negativity in 36-44% of patients.21,18

In patients with HBeAg-negative chronic hepatitis, lamivudine 100 mg/d orally for 1 year achieved HBV DNA negativity in 60-73% of patients.18

In both HBeAg-positive and HBeAg-negative patients, ALT levels and liver histology improved significantly. The rate of the development of hepatic fibrosis was reduced in a significant number of patients.

From early studies with lamivudine, it was learned that treatment in patients with HBeAg-positive chronic hepatitis should be continued for at least 6-12 months after patients achieved seroconversion from HBeAg-positive to anti-HBe positive. This helped to maximize the odds of maintaining a durable virologic response.

In patients with HBeAg-negative chronic hepatitis, however, it was learned that virologic relapse was almost invariable when treatment was discontinued. This led to the general dictum that patients with HBeAg-negative chronic hepatitis were likely to require indefinite treatment with a nucleoside analogue in order to keep viral loads suppressed.

The advantages of lamivudine over interferon included its ease of application and the virtual absence of adverse effects (see Warnings about therapy for HBV). Lamivudine was effective in populations whose HBV disease was generally not responsive to older formulations of IFN-alfa (eg, persons with high HBV DNA levels). Lamivudine was also successful in some patients with decompensated hepatitis B-induced cirrhosis and some patients with recurrent hepatitis B after liver transplantation.

Lamivudine received FDA approval for the treatment of chronic hepatitis B in adults in December 1998. However, problems with lamivudine therapy quickly became apparent. Approximately 24% of patients whose condition initially responded to lamivudine developed drug resistance within the first year of therapy. The incidence of lamivudine resistance increased to 69% after 5 years of therapy. This finding was explained by the development of a mutation at the YMDD locus in the HBV DNA polymerase gene. The development of lamivudine resistance occasionally led to a reversion of the improvements seen on some liver biopsy specimens.

Adefovir dipivoxil for chronic hepatitis B

Adefovir dipivoxil (HepSera; Gilead Sciences, Inc, Foster City, CA) is a synthetic nucleotide analogue. It received FDA approval for the treatment of chronic hepatitis B in adults in September 2002. This agent inhibits HBV DNA polymerase and causes DNA chain termination after its incorporation into viral DNA. It is typically dosed at 10 mg orally once per day. Dose adjustments should be made for patients with creatinine clearance <50 mL/min. Chronic use of adefovir dipivoxil has induced nephrotoxicity, particularly in patients with underlying renal dysfunction. It is recommended that patients undergo monitoring of their serum creatinine and phosphate while under treatment.

Adefovir dipivoxil 10 mg orally once per day for 48 weeks resulted in a mean drop in the HBV DNA by 3.52 log10 copies/mL in patients with HBeAg-positive chronic hepatitis and by 3.91 log10 copies/mL in patients with HBeAg-negative chronic hepatitis. In patients with HBeAg-positive chronic hepatitis, negative HBV DNA findings were achieved in 6% of patients by week 48 of treatment and 46% of patients by week 144 of treatment.22 In patients with HBeAg-negative chronic hepatitis, negative HBV DNA findings were achieved in 64% of patients by week 48 of treatment and 79% of patients by week 144 of treatment.23 Most HBeAg-positive and HBeAg-negative patients experienced improvements in both ALT and liver histology results while receiving adefovir dipivoxil.

Resistance mutations developed in less than 2% of patients taking long-term therapy with adefovir dipivoxil. The drug was also useful in patients who had previously developed resistance to lamivudine. Substitution of adefovir dipivoxil for lamivudine in such patients produced a 3-log10 drop in the number of HBV DNA copies/mL. Treatment with adefovir dipivoxil costs approximately $5300/y, as opposed to approximately $1700/y for lamivudine.

Entecavir for chronic hepatitis B

Entecavir (Baraclude; Bristol-Myers Squibb Company, New York, NY) is a deoxyguanine nucleoside analogue. It inhibits priming of HBV DNA polymerase with a resulting decrease in HBV replication. Entecavir received FDA approval for the treatment of chronic hepatitis B in adults in March 2005. It is dosed at 0.5 mg orally once per day in patients with HBeAg-positive and HBeAg-negative chronic hepatitis B. In patients with a history of lamivudine-resistant chronic hepatitis B, it is dosed at 1 mg orally once per day. As with adefovir dipivoxil, dose adjustments should be made for patients with creatinine clearance <50 mL/min and for patients receiving dialysis.

Entecavir 0.5 mg orally once per day for 48 weeks resulted in a mean drop in the HBV DNA by 6.98 log10 copies/mL in patients with HBeAg-positive chronic hepatitis and by 5.20 log10 copies/mL in patients with HBeAg-negative chronic hepatitis.24 By 48 weeks, a negative HBV DNA was achieved in 69% of HBeAg-positive patients and 91% of HBeAg-negative patients. These results were superior to patients who received lamivudine 100 mg once per day for 48 weeks.24 Currently, entecavir and tenofovir are regarded as first-line oral agents for patients with chronic hepatitis B.

Telbivudine for chronic hepatitis B

Telbivudine (Tyzeka; Novartis Pharmaceuticals Corp, East Hanover, NJ) received FDA approval in 2006. Telbivudine is a synthetic thymidine nucleoside analogue with activity against HBV DNA polymerase. By 52 weeks, treatment with telbivudine (600 mg/d) led to a reduction in HBV DNA by 6.45 log10 copies/mL in patients with HBeAg-positive chronic hepatitis and 5.23 log10 copies/mL in patients with HBeAg-negative chronic hepatitis. A negative HBV DNA was achieved in 75% of patients with HBeAg-positive chronic hepatitis and in 88% of patients with HBeAg-negative chronic hepatitis. Drug resistance was reported in 8-21% of patients.

Tenofovir disoproxil fumarate for chronic hepatitis B

Tenofovir disoproxil fumarate (Viread; Gilead Sciences, Inc., Foster City, Calif) received FDA approval for the treatment of hepatitis B in 2008. Previously, this agent had received approval for use in human immunodeficiency virus (HIV) infection. Like adefovir, tenofovir is an oral nucleotide analogue. It and entecavir are considered to be first-line oral agents for the treatment of chronic hepatitis B. As with adefovir, tenofovir has been associated with nephrotoxicity. Renal function should be monitored in patients under treatment.

Marcellin et al published their results comparing tenofovir to adefovir in patients with HBeAg-positive and HBeAg-negative chronic hepatitis B. Patients were randomized to receive either tenofovir 300 mg or adefovir 10 mg (ratio, 2:1) once daily for 48 weeks.25

At week 48 in HBeAg-positive patients, a serum HBV DNA <69 IU/mL (400 copies/mL) was achieved in 76% of patients randomized to tenofovir versus 13% of patients randomized to adefovir (P < 0.001).

At week 48 in HBeAg-negative patients, a serum HBV DNA <69 IU/mL (400 copies/mL) was achieved in 93% of patients randomized to tenofovir versus 63% of patients randomized to adefovir (P < 0.001).

Patients underwent liver biopsy before treatment and at 48 weeks of therapy. A histologic response — defined as a reduction in liver inflammation without worsening fibrosis — was seen in approximately 70% of patients treated with either tenofovir or adefovir (P >0.05). Drug resistance was not reported in any of the patients under treatment with tenofovir.

Combination therapy

Current data do not support the use of either a combination of interferon and a nucleoside analogue or a combination of 2 nucleoside analogues as first-line therapy for patients with chronic hepatitis B.26

After starting treatment with a nucleoside or nucleotide analogue, viral loads are typically followed every 3-6 months by a PCR assay. Combination therapy may be appropriate for patients who have had either a suboptimal response to first-line therapy or who have evidence for virologic breakthrough, defined as a 10-fold increase from the nadir HBV DNA level in a patient undergoing treatment.

Virologic breakthrough is often the hallmark of the development of virologic resistance to drug therapy. Such an event might necessitate either a switch to a new oral analogue with no cross-resistance to the first drug or the addition of a second oral agent to the original regimen. The subject of combination therapy is an evolving topic. Some recommendations for the management of drug-resistant HBV infection are contained within the practice guidelines of the American Association for the Study of Liver Diseases7 and in Keeffe et al’s “treatment algorithm.”

Management of HBV carriers undergoing chemotherapy or immunosuppression.

Reactivations of HBV infection in a common event in HBV carriers who undergo either chemotherapy or immunosuppression for another indication. Typically, this is described in patients who are already HBsAg positive. However, HBV reactivation is described in patient who are anti-HBc positive, with a negative HBsAg and a positive anti-HBs. HBV reactivation in these circumstances has the potential to be severe or even life-threatening.

The practice guidelines of the American Association for the Study of Liver Diseases recommend that HBV carriers with a baseline HBV DNA <2000 IU/mL undergo prophylactic antiviral therapy during their treatment and for 6 months after the conclusion of chemotherapy or a finite course of immunosuppressive therapy. Patients with a higher baseline HBV DNA should be treated until “they reach treatment endpoints as in immunocompetent patients.”

Warnings about therapy for HBV

Patients should undergo testing with a PCR-based assay for HBV DNA before therapy is started. Viral loads may range from undetectable to hundreds of millions of IU/mL. Antiviral therapy is generally reserved for patients with greater than 104 IU/mL for patients with HBeAg-positive chronic hepatitis. A lower HBV DNA, perhaps 103 IU/mL, may be an appropriate trigger to initiate therapy in patients with HBeAg-negative chronic hepatitis (ie, patients with precore mutant viruses).

Lactic acidosis and severe hepatomegaly with steatosis have been reported rarely in patients undergoing treatment with lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil fumarate. Severe acute exacerbations of hepatitis have been reported infrequently in patients who discontinue antiviral therapy. Thus, patients continuing treatment and patients who discontinue treatment require careful monitoring.

HBV vaccine

Plasma-derived and recombinant HBV vaccines use HBsAg to stimulate the production of anti-HBs ioninfected individuals. The vaccines are highly effective, with a greater than 95% rate of seroconversion. Vaccine administration is recommended for all infants and for adults at high risk of infection (eg, those receiving dialysis, healthcare workers).

The recommended vaccination schedule for infants is an initial vaccination at the time of birth (ie, before hospital discharge), repeat vaccination at 1-2 months, and another repeat vaccination at 6-18 months. The recommended vaccination schedule for adults is an initial vaccination, a repeat vaccination at 1 month, and another repeat vaccination at 6 months. Dosing of Twinrix, the combined hepatitis A and hepatitis B vaccine, is as described above (see Hepatitis A).

HBV infection is endemic in Taiwan. Institution of universal vaccination for neonates in 1984 decreased the HBsAg carrier rate in children from 9.8% to 0.7%, 15 years later.27 There was a resulting drop in the incidence of HCC in children from 0.54 to 0.20 per 100,000.27 We await follow-up studies to see if the overall incidence of HCC decreases in Taiwan as these children enter adulthood.

Postexposure prophylaxis

Hepatitis B immune globulin (HBIG) is derived from plasma. It provides passive immunization for individuals who describe recent exposure to a patient infected with HBV. HBIG is also administered following liver transplantation to persons infected with HBV, in order to prevent HBV-induced damage to the liver allograft. Recommendations for postexposure prophylaxis for contacts of patients positive for HBsAg are as follows:

• Perinatal exposure – HBIG plus vaccination at time of birth (90% effective)
• Sexual contact with an acutely infected patient – HBIG plus vaccination
• Sexual contact with a chronic carrier – Vaccination
• Household contact with an acutely infected patient – None
• Household contact with an acutely infected person resulting in known exposure – HBIG with or without vaccination
• Infant (<12 mo) primarily cared for by an acutely infected patient – HBIG with or without vaccination
• Inadvertent percutaneous or permucosal exposure – HBIG with or without vaccination

Hepatitis C

HCV is a flavivirus. It is a 9.4-kb RNA virus with a diameter of 55 nm. It has one serotype and multiple genotypes. HCVs have profound genetic variability throughout the world. At least 6 major genotypes and more than 80 subtypes are described, with as little as 55% genetic sequence homology. Genotype 1b is the genotype most commonly seen in the United States, in Europe, in Japan, and in Taiwan. Genotypes 1b and 1a (also common in the US) are less responsive to interferon therapy than other HCV genotypes. The genetic variability of HCV hampers the efforts of scientists to design an effective anti-HCV vaccine.

Epidemiology of hepatitis C

Hepatitis C is prevalent in 0.5-2% of populations iations around the world. An estimated 4 million Americans are infected with HCV. In the 1980s, as many as 180,000 new cases of HCV infection were described each year in the US. By 1995, there were only 28,000 new cases each year.28 The decreasing incidence of HCV was explained by a decline in the number of cases of transfusion-associated hepatitis (because of improved screening of blood products) and by a decline in the number of cases associated with intravenous drug use.

Transmission of HCV via blood transfusion

Screening of the US blood supply has dramatically reduced the incidence of transfusion-associated HCV infection. Before 1990, 37-58% of cases of acute HCV infection (then known as NANB) were attributed to the transfusion of contaminated blood products. Now, only approximately 4% of acute cases are attributed to transfusion. HCV is estimated to contaminate 0.01-0.001% of units of transfused blood. Acute hepatitis C remains an important issue in dialysis units, where patients’ risk for HCV infection is approximately 0.15% per year.

Transmission of HCV via intravenous and intranasal drug use

Intravenous drug use remains an important mode of transmitting HCV. Intravenous drug use and the sharing of paraphernalia used in the intranasal snorting of cocaine and heroin account for approximately 60% of new cases of HCV infection. More than 90% of patients with a history of intravenous drug use have been exposed to HCV.

Transmission of HCV via occupational exposure

Occupational exposure to HCV accounts for approximately 4% of new infections. On average, the chance of acquiring HCV after a needle-stick injury involving an infected patient is 1.8% (range, 0-7%). Of importance, reports of HCV transmission from healthcare workers to patients are extremely uncommon.

Transmission of HCV via sexual contact

Approximately 20% of cases of hepatitis C appear to be due to sexual contact. In contrast to hepatitis B, approximately 5% of the sexual partners of those infected with HCV contract hepatitis C. The US Public Health Service recommends that persons infected with HCV be informed of the potential for sexual transmission. Sexual partners should be tested for the presence of anti-HCV. Safe-sex precautions are recommended for patients with multiple sex partners. Current guidelines do not recommend the use of barrier precautions for patients with a steady sexual partner. However, patients should avoid sharing razors and toothbrushes with others. In addition, contact with patients’ blood should be avoided.

Transmission of HCV via perinatal transmission

Perinatal transmission appears to be uncommon. It is observed in fewer than 5% of children born to mothers infected with HCV. The risk of perinatal transmission of HCV is higher, estimated at 18%, in children born to mothers coinfected with HIV and HCV.29 Available data show no increase in HCV infection in babies who are breastfed. The US Public Health Service does not advise against pregnancy or breastfeeding for women infected with HCV.

Natural history of chronic hepatitis C

Approximately 15-30% of patients acutely infected with HCV lose virologic markers for HCV. Thus, approximately 70-85% of newly infected patients remain viremic and may develop chronic liver disease. In chronic hepatitis, patients may or may not be symptomatic, with fatigue being the predominant reported symptom. Aminotransferase levels may fluctuate from the reference range (<40 U/L) to 300 U/L. However, no clear-cut association exists between aminotransferase levels and symptoms or risk of disease progression.

Natural history of cirrhosis induced by hepatitis C

An estimated 20% of patients with chronic hepatitis C experience progression to cirrhosis. This process may take 10-40 years to evolve. Importantly, patients who are newly diagnosed with well-compensated cirrhosis must be counseled regarding their risk of developing symptoms of liver failure (ie, decompensated cirrhosis). Only 30% of patients with well-compensated cirrhosis are anticipated to decompensate over a 10-year follow-up period.

Patients with HCV-induced cirrhosis are also at increased risk for the development of HCC, especially in the setting of HBV coinfection. In the United States, HCC arises in 3-5% of patients with HCV-induced cirrhosis each year. Accordingly, routine screening (eg, ultrasonography and AFP testing every 6 mo) is recommended in patients with HCV-induced cirrhosis to rule out the development of HCC.

End-stage liver disease caused by HCV leads to about 10,000 deaths in the US each year.

 

Triple phase computed tomography scan of a liver cancer, revealing classic findings of enhancement during the arterial phase and delayed hypointensity during the portal venous phase

 

Extrahepatic manifestations of hepatitis C

Patients with chronic hepatitis C are at risk for extrahepatic complications. In essential mixed cryoglobulinemia, HCV may form immune complexes with anti-HCV (IgG) and with rheumatoid factor (RF). The deposition of immune complexes may cause small-vessel damage. Complications of cryoglobulinemia include rash, vasculitis, and glomerulonephritis. Other extrahepatic complications of HCV infection include focal lymphocytic sialadenitis, autoimmune thyroiditis, porphyria cutanea tarda, lichen planus, and Mooren corneal ulcer. Some cases of non-Hodgkin lymphoma can be attributed to hepatitis C infection.

Pathologic findings of hepatitis C

Lymphocytic infiltrates, either contained within the portal tract or expanding out of the portal tract into the liver lobule (interface hepatitis), are commonly observed in patients with chronic hepatitis C. Portal and periportal fibrosis may be present. Other classic histologic features of the disease include bile duct damage, lymphoid follicles or aggregates, and macrovesicular steatosis.

Pathologists who interpret liver biopsy specimens frequently use a histologic scoring system introduced by Batts and Ludwig in 1995, which is displayed in Table 2 below.³⁰ The METAVIR scoring system (developed by the French METAVIR Cooperative Study Group) uses similar methodology.

Histologic Grading for Hepatitis C-Induced Liver Disease

Grade	Portal Inflammation	Interface Hepatitis	Lobular Necrosis
1 – Minimal	Mild	Scant	None
2 – Mild	Mild	Mild	Scant
3 – Moderate	Moderate	Moderate	Spotty
4 – Severe	Marked	Marked	Confluent
Grade	Portal Inflammation	Interface Hepatitis	Lobular Necrosis
1 – Minimal	Mild	Scant	None
2 – Mild	Mild	Mild	Scant
3 – Moderate	Moderate	Moderate	Spotty
4 – Severe	Marked	Marked	Confluent

The histologic staging for hepatitis C–induced liver disease is as follows:

Stage 1: portal fibrosis

Stage 2: periportal fibrosis

Stage 3: septal fibrosis

Stage 4: cirrhosis

Diagnosis of hepatitis C

The most common tests used in the diagnosis of hepatitis C include liver chemistries, serologic tests, HCV RNA tests, and liver biopsies.

Diagnosis of hepatitis C using liver chemistry testing

Elevations of AST and ALT levels merely indicate the presence of liver injury. Patients with chronically elevated aminotransferase values should undergo a workup to exclude the possibility of chronic liver disease.

Measuring aminotransferase levels is an imperfect test in patients with documented HCV infection. The values do not predict the severity of clinical findings, the degree of histologic abnormalities, the patient’s prognosis, or the therapeutic response. Indeed, patients can have HCV-induced cirrhosis and have normal liver chemistry values. Increases and decreases in aminotransferase levels do not appear to correlate with clinical changes. However, normalization of AST and ALT levels following acute infection may signal clearance of HCV. Normalization of AST and ALT levels while a patient is undergoing treatment with interferon predicts a virologic response to treatment. Similarly, an increase in AST and ALT values may signal a relapse after apparently successful drug therapy.

Diagnosis of hepatitis C using serologic tests for HCV

Structural and nonstructural regions of the HCV genome have been synthesized. These can be recognized by human IgG anti-HCV. Recombinant HCV antigens are used in enzyme-linked immunosorbent assay (ELISA) to detect anti-HCV in patients’ sera.

Anti-HCV test results remaiegative for several months following acute HCV infection. After its appearance, the anti-HCV usually remains present for the life of the patient. This occurs even in the 15% of cases in which the patient clears the virus and does not develop chronic hepatitis. Anti-HCV is not a protective antibody and does not guard against future exposures to HCV.

The US Food and Drug Administration has approved OraQuick HCV Rapid Antibody Test.31 The test can be used for persons at risk for hepatitis or for those with signs or symptoms of hepatitis. The test strip can be used with a sample collected from oral fluid, whole blood, serum, or plasma.

Recombinant immunoblot assays (RIBAs) use recombinant HCV antigens that are fixed to a solid substrate. They are more specific than ELISA testing and have been used to confirm positive ELISA results. However, their use is being abandoned in favor of HCV RNA testing.

A positive HCV result with ELISA or recombinant immunoblot assay (RIBA) has 1 of 3 potential interpretations. First, the test result is a true positive, and the patient is infected with HCV. Second, the test result is a true positive, but the patient is no longer viremic for HCV and does not have chronic hepatitis. The results from neither the ELISA nor the RIBA distinguish resolved infection from active infection. Third, the test result is a false positive.

ELISA testing has a positive predictive value (PPV) of greater than 95% when it is used in patients at high risk for hepatitis C, such as individuals who use intravenous drugs and have abnormal liver chemistry findings. However, the positive predictive value is only 50-61% in patients who are at low risk for HCV infection. Furthermore, patients with autoimmune hepatitis or hypergammaglobulinemia frequently have false-positive ELISA test results. Thus, a positive HCV ELISA or RIBA test result does not prove the presence of HCV infection. Positive serologic tests require confirmation with HCV RNA testing.

Other limitations of ELISA testing include that it fails to detect anti-HCV in 2-5% of infected patients, and it fails to detect anti-HCV in immunosuppressed patients, such as patients with end-stage renal disease, HIV infection, or concomitant immunosuppressant therapy. The possibility of HCV infection in this patient population should prompt HCV RNA testing.

Diagnosis of hepatitis C using HCV RNA tests

PCR assays and branched DNA assays have been used since the early 1990s to detect HCV RNA in serum. In contrast to ELISA and RIBA testing, HCV RNA testing can confirm the presence of active HCV infection.

HCV RNA testing has a number of important uses. It aids in the diagnosis of (1) early cases of HCV infection, before the development of HCV antibody positivity or an elevation of the ALT level; (2) seronegative cases, such as in the setting of end-stage renal disease; and (3) cases of perinatal transmission. HCV RNA testing also helps to (1) confirm false-positive cases, such as autoimmune hepatitis; (2) assess the HCV genotype and viral load; (3) predict the response to interferon therapy; (4) guide the duration and dose of interferon therapy; and (5) assess the likelihood of relapse following a response to interferon therapy.

Diagnosis of hepatitis C using liver biopsy

Liver biopsy is an important diagnostic test in possible cases of chronic hepatitis C. Biopsy results can help confirm the diagnosis as well as help exclude other diseases that might have an impact on antiviral therapy, such as autoimmune hepatitis or hemochromatosis. Furthermore, liver biopsy offers the most reliable assessment of the severity of disease.

Assessment of the degree of hepatic fibrosis is important for a number of reasons. Determination of the presence of “advanced fibrosis” — ie, or stage 3 or stage 4 disease — might lead to a decision to initiate screening tests to rule out the interval development of HCC as a complication of advanced liver disease. Patients with previously unsuspected cirrhosis on biopsy should also be monitored to ensure they do not develop large esophageal varices. In the authors opinion, patients with stage 3 fibrosis should be regarded as “being cirrhotic until proven otherwise.”

Knowledge of the severity of histologic changes may influence the patient and the physician to be more aggressive or less aggressive in the pursuit of effective antiviral therapy. Determination of the presence of “significant fibrosis” — ie, stage 2, 3, or 4 disease — might lead to a decision to initiate antiviral therapy. The hope is that eradication of HCV will help to improve the patient’s long-term outcome. Patients with advanced histologic findings may seek experimental therapies should their conditioot respond to standard antiviral therapy.

Patients with minimal fibrosis on biopsy (ie, stage 1 disease) might elect to either receive antiviral therapy or postpone therapy. Indeed, the patient with stage 1 disease might be felt to be at low risk for complications of HCV infection. Furthermore, the risks of therapy might exceed benefits in such a patient, (eg, a patient with HCV infection, stage 1 fibrosis and major depression).

Before patients with stage 1 fibrosis elect to undergo a course of watchful waiting, the author counsels his patients that only virologic eradication can ensure that the patient never develops one of the extrahepatic complications of hepatitis C. The author also advises his patients to return for a repeat biopsy in 3-4 years to rule out progression of liver disease.

Liver biopsy has a number of noteworthy limitations. First, as an invasive procedure, it may be accompanied by significant complications (eg, bleeding) in approximately 1 in 1000 patients. Second, a sampling error may occur. Indeed, the damage induced by viral infection in some patients is not uniform throughout the entire liver. Also, interobserver variability may occur when assessing histologic abnormalities. Finally, as a snapshot in time, liver biopsy findings cannot be used to predict the rate of progression of chronic hepatitis C.

Radiologic and serologic and tests for estimating the degree of fibrosis in patients with chronic hepatitis C

For the last several years, clinicians have been able to assess liver stiffness through an ultrasound technique known as Fibroscan (Echosens SA, Paris, France). It is reported that cirrhosis can be diagnosed correctly in about 95% of patients. The test is less accurate in assessing patients with lesser degrees of fibrosis.32 Fibroscan is not currently licensed for use in the United States.

Liver fibrosis can also be estimated by means of a number of commercial blood tests. FIBROSpect II (Prometheus Laboratories, San Diego, Calif) uses measurements of hyaluronic acid, TIMP-1 and alpha-2 macroglobulin to estimate liver fibrosis. HepaScore (Quest Diagnostics, Madison, NJ) is based on levels of hyaluronic acid, alpha-2 macroglobulin, gamma glutamyl transferase (GGT), and total bilirubin, as well as age and gender. HCV FIBROSURE (LabCorp, Burlington, NC) measures alpha-2 macroglobulin, haptoglobin, GGT, bilirubin, ALT and apolipoprotein A1. In general, it is contended that these tests are accurate in determining the presence or absence of early (stage 1) or advanced (stage 4) fibrosis. However, these tests are less accurate when it comes to differentiating patients with moderate fibrosis.

Given these limitations, most gastroenterologists do no currently use serologic fibrosis markers as a substitute for liver biopsy. These tests may be useful in current practice for identifying patients at low risk for advanced disease (eg, asymptomatic women with HCV RNA positivity, persistently normal liver chemistry values, and no history for alcohol abuse or HIV infection). They may also be useful in the longitudinal follow-up of patients with minimal disease on biopsy specimens who have elected to not undergo antiviral therapy. Future generations of serologic fibrosis markers may have greater accuracy and may obviate the need for liver biopsy.

Treatment of chronic hepatitis C: results of clinical trials

http://www.bmj.com/content/323/7322/1141.full

IFN-alfa-2b, dosed at 3 million U subcutaneously 3 times per week, was approved by the FDA in 1991 for the treatment of chronic HCV infection. Patients treated with this interferon, and with subsequently introduced IFN-alfa-2a and consensus interferon, had only an 11-12% chance of obtaining a SVR (ie, a persistently undetectable HCV RNA level).

The combination of ribavirin, a nucleoside analogue, with interferon significantly improved patients’ responses to treatment. The SVR after 48 weeks of treatment improved from 13% in patients treated with IFN-alfa-2b alone to 38% in patients treated with IFN-alfa-2b in combination with ribavirin at 1000-1200 mg/d orally.39 So-called combination therapy received approval from the FDA in 1998.

Another major breakthrough came in 2000 with the FDA approval of PEG-IFN-alfa-2b in combination with ribavirin. PEG-IFN-alfa-2a received FDA approval in 2002. By delaying drug clearance from the bloodstream, pegylation allows each interferon to be administered subcutaneously once per week. Higher interferon blood levels are achieved when PEG-IFN is dosed once per week than when standard interferon is dosed 3 times per week.

Typical dosing of PEG-IFN-alfa-2b is 1-1.5 mcg/kg/wk subcutaneously. PEG-IFN-alfa-2a is dosed at 180 mcg/wk. Typical ribavirin dosing is in the range of 800-1200 mg/d in 2 divided doses.

Studies with PEG-IFN-alfa-2b and ribavirin showed a 42% SVR rate in patients with genotype 1 who were treated for 48 weeks. An 82% SVR was achieved in patients with genotypes 2 and 3.40 In the case of PEG-IFN-alfa-2a and ribavirin, a 46% SVR was achieved in patients with genotype 1 who were treated for 48 weeks. A 76% SVR was achieved in patients with genotypes 2 and 3.41

The 2 currently available PEG-IFNs appear to be relatively equivalent in terms of their efficacy and tolerability in patients with HCV genotype 1. The recently published IDEAL trial (Individualized Dosing Efficacy vs Flat Dosing to Assess Optimal Pegylated Interferon Therapy) randomized previously untreated patients with HCV genotype 1 to either PEG-IFN-alfa-2b or PEG-IFN-alfa-2a, in combination with ribavirin.42 Treatment with PEG-IFN-alfa-2b at a dose of 1.5 mcg/kg/wk produced a 40% SVR rate. Treatment with PEG-IFN-alfa-2a produced a 41% SVR rate. Surprisingly, treatment with low-dose PEG-IFN-alfa-2b at 1 mcg/kg/wk produced a 38% SVR rate. These results were not significant statistically.42

Factors predictive of an SVR to treatment with PEG-IFN in combination with ribavirin include (1) genotype 2 or 3 status, (2) a baseline HCV RNA level <800,000 IU/mL or <2 million copies/mL, (3) compliance with treatment, and (4) absence of cirrhosis. However, patients with well-compensated cirrhosis now have a reasonable likelihood of achieving viral eradication and should be offered interferon therapy, provided no significant contraindication (eg, severe thrombocytopenia) is present. Ideally, HCV eradication in the cirrhotic patient may prevent or forestall the development of progressive hepatic fibrosis and liver decompensation. Patients treated with interferon may also have a decreased risk for HCC. Should a patient ultimately require liver transplantation for the treatment of complications of cirrhosis, previous eradication of the hepatitis C virus obviates any concerns about potentially severe recurrent hepatitis C after transplantation.

Treatment of chronic hepatitis C: practical issues

Patients who are infected with HCV genotype 1 and 4 typically undergo treatment for 48 weeks. Patients who are infected with HCV genotype 2 or 3 typically undergo treatment for 24 weeks. HCV RNA levels are usually rechecked 1 month and 3 months after starting treatment and every 3 months thereafter.43

In HCV genotype 1 cases, patients who achieve a viral load negativity 1 month into treatment – also known as a rapid virologic response (RVR) – have a greater than 90% likelihood of achieving an SVR. The more typical situation is that patients remain HCV RNA positive at 1 and 3 months. If treatment cannot induce a 2-log10 drop in the viral load from baseline by week 12, the likelihood that the patient will achieve a SVR is less than 3%. Many physicians advise discontinuation of therapy in such patients in whom an early virologic response does not occur.44

Longer durations of therapy, up to 72 weeks, may be appropriate in patients infected with genotype 1 who are slow responders (ie, patients who achieved a 2-log10 drop in the viral load but did not achieve an undetectable HCV RNA level by week 12). In one study, a SVR rate of 38% was seen in slow responders who continued treatment for 72 weeks, contrasted with the SVR rate of 18% seen in slow responders who received treatment for the traditional 48 weeks.

Recent trials explored the utility of shortened courses of PEG-IFN and ribavirin for patients with genotypes 2 and 3. Although SVR may be achieved in some patients with as little as 12 to 16 weeks of therapy, overall SVR rates may be diminished. Thus, shortened treatment courses cannot be recommended for patients with genotypes 2 and 3 at this time.33

Repeat treatment of patients who were nonresponsive to antiviral therapy

Approximately 11% of patients whose HCV disease was nonresponsive to interferon and ribavirin combination therapy can achieve an SVR when treated with PEG-IFN in combination with ribavirin. A more vexing issue is the treatment of patients whose disease was nonresponsive to PEG-IFN in combination with ribavirin.

Previously, chronic maintenance therapy with low dose PEG-IFN was considered for patients with advanced fibrosis who were virologic nonresponders but had achieved some reduction in viral load while under treatment. However, neither the HALT-C trial (utilizing PEG-IFN-alfa-2a) nor the COPILOT trial (utilizing PEG-IFN-alfa-2b) were able to demonstrate any decrease in the incidence of liver decompensation, HCC or liver-related death in patients undergoing maintenance therapy.

For several years, high-dose daily consensus interferon, in combination with ribavirin, has been used in patients with HCV genotype 1 who were nonresponders to standard treatment with pegylated interferon and ribavirin. Results of the DIRECT trial were recently reported. Daily consensus interferon at a doses of 9 mcg or 15 mcg was used in combination with ribavirin in nonresponders to treatment with pegylated interferon. In the 15 mcg group, 11% of patients achieved SVR. However, when patients who had previously achieved a >2-log₁₀ decrease in HCV RNA were assessed, the SVR rate improved to 23% in the 15 mcg group. High-dose daily-consensus interferon and ribavirin recently received FDA approval for re-treatment of patients with chronic hepatitis C who were nonresponders to pegylated interferon and ribavirin.

MALARIA

http://health.nytimes.com/health/guides/disease/malaria/overview.html

Definition

Malaria (from the colloquial Italian “mala” – bad, and “aria” – air) is an infection characterized by certain febrile disturbances caused by protozoan parasites of the class Sporozoa and of the family Plasmodiidae. Man is the intermediate host of these parasites, which undergo an asexual stage of development in the red corpuscles. The Parasite undergoes a sexual phase of development in the Anopheles mosquito, which is hence the definitive host. Man acquires infection from the bite of such an infected mosquito. Clinically, malaria is characterized by periodic attacks of fever, associated with anemia and enlargement of the spleen, and if untreated, with cachexia and a deposit of black pigment in the various organs. The malady is amenable to treatment with quinine and several other synthetic compounds inimical to the life of the parasite.

 

History

Malaria was formerly supposed to be due to poisonous emanations from damp ground, hence the term “malaria,” introduced into English literature about 1829. Hippocrates, 460-370 B.C., in his book on epidemics, noted the existence of periodic fevers, divided them into quotidian, tertian, quartan, and subtertian, and referred to the enlarged spleen. Celsus recognized 2 types of tertian fever, one benign and similar to quartan fever, the other in which the attack is of longer duration and far more severe in character, the fever occupying 36 of the 48 hours and not entirely subsiding in the remissions, but being only mitigated.

Columella, about 116 B.C., suggested that the virus of malaria emanated from marshes and associated the disease with insects originating in them which attacked man in swarms. Also in the time of Caesar, views were expressed by Varro that swamp air might be the cause of malaria and furthermore that animals, so small that the eye could not follow them, might transmit diseases by way of the mouth or nose. In view of our present knowledge, it is remarkable that Lancisi. in 1718, should have associated marshes with the development of gnats, which insects he thought could not only introduce with their proboscides the putrefying organic matter of such swamps, but animalcules as well.

In 1638, Countess del Chinchon, wife of the Viceroy of Peru, was cured of an intermittent fever by treatment with the bark of a certain tree, which bark was introduced into Europe in 1640. Linne, who named the genus of quinine-producing about 100 years later, left out the first «h» in the name, hence the mistaken spelling Cinchona.

Discovery of the Parasite

The year 1880 was a most important one in the history of malaria, for on November 6, 1880, Laveran, at Constantine, first recognized the parasites of malaria while carrying on investigations as to the origin of the “pigmented bodies” and pigmented leukocytes. He observed not only spherical pigmented bodies, but also crescents, and in particular the flagellation of the male gamete, which demonstrated to him that these were living organisms. He proposed the name Oscillaria malarias on account of the movements of the flagellate body, but this had to be dropped as not valid, the generic name Oscillaria having been previously applied to another organism.

In 1894 Manson formulated the hypothesis of the mosquito transmission of malaria. He based this upon facts he observed in tracing the life-history of filaria and upon the fact that in malaria the flagellation of the male gametocyte does not take place for several minutes after the removal of the blood from the peripheral circulation. He also suggested that larvae might feed upon infected mosquitoes dying upon the water and thus acquire the disease.

Ross for 2 years caused mosquitoes to feed upon the blood of malarial patients which contained crescents, but as he used insects of the genera Culex and Aedes no development of the parasites in the tissues of the mosquitoes occurred, m 1897 he used eight dappled-wing mosquitoes (Anopheles Stephens) and in 2 of these, upon dissection, he noted the development of the pigmentary bodies to be different from anything he had observed in hundreds of dissections of other mosquitoes.

In 1886 Metschnikoff, from observation of sporulating parasites in the brain capillaries at the autopsy of a malarial case, considered them to be coccidial iature.

Four parasites, all of this genus, may give rise to malaria in man; the names of the species are Plasmodium vivax which produces benign tertian malaria, Plasmodium malarias of quartan malaria, Plasmodium ovate another tertian parasite, and Plasmodium falciparum, which causes malignant tertian malaria. Each of these species shows the following characters which are possessed by the genus, as it affects man.

Before proceeding to study the parasites there are certain terms which require definition.

Life history

This comprises two cycles or phases of development:

a)                schizogony in the tissues of man, which is succeeded by schizogony occurring in the blood stream of man ; these form the asexual cycle of the parasite ;

b)               sporogony, the sexual cycle, which occurs in the body of an anopheline mosquito.

 

Cycles  of Plasmodium development

Schizogony. When the sporozoite is introduced into man’s skin by the bite of an anopheline mosquito it passes into the blood stream from which it rapidly disappears to enter a parenchyma cell of the liver. Here a process of growth and multiplication occurs, known as preerythrocytic schizogony, which results in the development of a large schizont, measuring up to 60m in diameter and containing thousands of tiny merozoites less than 1m in size. The mature schizont ruptures about the seventh to the ninth day liberating the merozoites which enter the circulation and invade red blood corpuscles. This starts the phase of erythrocytic schizogony which, however, may not become demonstrable by the examination of blood films until one or two days later.

Erythrocytic schizogony occurs in the circulation and extends from the newly liberated merozoite which is ready to infect a fresh cell, to the rupture of the mature schizont with its contained daughter merozoites. This cycle occupies a period of  forty-eight hours in P. vivax, ovale, falciparum and seventy-two in P. malaria, for its completion. The merozoites attack fresh cells, and in them develop into rings, after which the parasites grow through the large trophozoite stage, attain full size, and then proceed to reproduce by division. As soon as this has commenced, when there is evidence that the nucleus has divided and the cytoplasm begun to segment, the term “immature schizont” is applied. Later, when the parasite has reached the stage at which it is fully segmented, and when the merozoites are just about to be liberated by the disruption of the red cells, it is called a “mature schizont” The distended cell ruptures, and the merozoites are thus liberated into the plasma. The residual material is at the same time set free, and, with its contained pigment, is quickly ingested by fixed endothelial cells of the blood vessels, or by wandering phagocytes, usually large mononuclears. Such pigmented leukocytes may be found in stained films if the blood is examined soon after the schizonts have ruptured. The liberated merozoite contains no pigment, immediately enters a fresh red cell and starts the cycle again. As a result of repetition of the erythrocytic cycle and progressive invasion of fresh cells, the infected person in the course of ten days or so develops fever; the period of incubation may, however, be shorter or much longer than this.

There is strong indirect evidence to suggest that in the case of P. vivax, P. ovale and P. malaria the tissue phase of the parasite does not end with the rupture of the pre-erythrocytic schizont and the invasion of the circulation by its merozoites. It is believed that a cycle, known as exoerythrocytic schizogony, continues in the tissues, some of the liberated merozoites invading fresh liver cells and again proceeding to schizogony. According to this hypothesis, even when parasites are absent from the blood, schizogony is continuing repeatedly in the tissues, persisting often for years. On occasions merozoites are discharged into the circulation where they infect red blood corpuscles and thus recommence erythrocytic schizogony, causing parasitaemia. No such evidence exists in the case of P. falciparum, and it is thought that when the preerythrocytic schizonts of this species have discharged their merozoites into the blood stream the cycle of the parasite in the tissues ends.

Sporogony. The sexual or sporogony cycle occurs almost entirely in the Anophelis mosquito. In this method of reproduction there are, however, as we saw, preliminary, and also terminal, stages in the blood. Certain merozoites, instead of repeating the asexual cycle, become gametocytes, of which some are male and some are female. These are found in the peripheral blood. If they are taken up by the mosquito in biting, further development very quickly occurs, the remains of the infected red cell being discarded during the process. The asexual parasites ingested with the blood by the mosquito are destroyed in the gut; it is only the gametocytes which survive, and are able to infect the insect. In the case of P. falciparum, as we saw, the gametocytes are crescent-shaped, and the first step in the development is that they assume a rounded form like those of P. vivax and P. malarias. The next step is, that in the male, or microgametocyte, the pigment is suddenly observed to be in violent commotion and soon several filaments are extruded each of which contains a granule of the nuclear chromatin. These are extremely active, and it is they which caused the rapid movements of the pigment granules. They detach themselves and swim away; these are the male gametes or the microgametes, which correspond to spermatozoa. The female or macrogametocyte has meanwhile undergone a nuclear reduction process by which it is transformed into the female gamete or macrogamete. This is an unfertilized ovum, and it attracts the active microgametes, one of which penetrates and fertilizes it. After this, the ovum or zygote, as it is now called, is capable of slow movements and hence is known as an “ookinete”. This passes between the cells lining the insect’s gut, till it reaches the outer limiting membrane. It then ceases to move, becomes round and proceeds to grow, the membrane acting as a cyst wall. This stationary growing ookinete with its covering is called the oocyst, and it grows from about 6 to 60 nm in size. Since the zygote is simply the female malaria parasite after fertilization by the filamentous male gamete, there is still some pigment in it, and this can be detected inside the oocyst. The nucleus of the zygote divides repeatedly, and finally there are produced, inside the oocyst, thousands of minute thread-like structures called sporozoites. When the oocyst becomes mature it ruptures, and the contained sporozoites are set free in the insect’s haemocoele, the circulation of which carries them to all parts of the mosquito’s body.

Some of them invade the cells of the salivary glands, pass through them and reach the lumen, which communicates with the salivary ducts. The mosquito is now infective. When next it bites man, the salivary fluid containing the sporozoites passes into the skin wound. A mosquito may acquire and be able to transmit a double infection. It is possible for a single infective mosquito to transmit malaria to several people in succession, and at considerable intervals. The supply of sporozoites in the salivary ducts is replenished by a further passage of those in the hemocoele, through the gland cells, into the lumen.

The sporozoite is a narrow, slightly curved organism, measuring about 12 nm in length; it tapers at both ends, has an elongated central nucleus and is devoid of pigment. It is capable of slight undulatory movement As already noted, when it is inoculated into man it is carried in the blood stream to the cells of the liver, which it enters; there it rounds up, starts to grow, and so commences the asexual cycle in man.

The sexual cycle in the mosquito requires about eight to eighteen days for completion, depending on conditions such as moisture and temperature. In the case of P. malarias the sexual cycle in the mosquito is commonly as long as four weeks.

The asexual cycle can be started in a person otherwise than by the bite of an infective mosquito, for example, by inoculating blood which contains asexual forms, into a fresh subject. If it happens that the only forms present in the infected person’s blood are gametocytes, such as the crescents of malignant tertian malaria, no infection will result, as these can only infect the mosquito, and do not infect man.

Epidemiology and endemiology

Conditions which favour the presence and breeding of anopheles mosquitoes tend to the increase of malaria, and vice versa, and, whatever favors access of those insects and the parasites they contain, also favours the acquisition of malaria.

In subtropical regions subtertian malaria is a primary infection in summer and early autumn, hence the popular term – cestio-autumnal fever. This peculiarity can be explained to some extent by the higher atmospheric temperature required for its development in the mosquito. Hence, though benign and subtertian forms are frequently associated, and the latter can be acquired at any time in the tropics, it is only in the summer and early autumn that subtertian can be acquired in more temperate zones. When the temperature falls below 15° C. development of the oocyst in the mosquito is arrested, but when once the sporozoites have entered the salivary glands, they are capable of infecting man, even during the winter season.

Malaria incidence is usually endemic, but hyperendemicity is a distinct form, demanding for its production such an intensity of transmission that a high degree of tolerance to the effects of reinfection is induced in those who experience its effects over a number of years, especially as a result of repeated infections in early childhood.

The World Health Organization has proposed the following classification:

I. Hypoendemic Malaria with spleen rate in children 2-10 years of age 0-10 %

II. Mesoendemic Malaria with spleen rate in children 2-10 years of age 11-50 %

III, Hyperendemic Malaria with spleen rate in children 2-10 years of age constantly over 75 %. Spleen rate in adults is also high.

IV. Holoendemic Malaria with spleen rate in children 2-10 years of age constantly over 75 5. Spleen rate in adults low; it is in this type of endemicity that the strongest adult tolerance is found.

Favourable season for malaria

A.   Sporogony in mosquito organism

B.    Tissue schizogony

C.   Erythrocytar schizogony

Morbid anatomy and pathology of malaria

The pathology of malaria is based really upon subtertian infections (P. falciparum). Most of the lesions in the internal organs are due to infection of red blood corpuscles with consequent disturbance of the oxygen supply to the tissues. The vascular flow within the organs is disturbed by vascular collapse, obstruction of the smaller vessels by auto-agglutination, thrombosis, infarctions and similar effects brought about by the clumping together of parasitised cells. All these factors slow down the circulation and cause “ludging” (Knisely) which is thought to be mainly due to the production of a fibrin-like substance. Cardiac and vascular failure may ensue. In addition there are explosive discharges of protein from the liberated merozoites and the disintegration of disrupted red cells, defunct parasites and extrusion of pigment. The spleen, when grossly enlarged, used to be popularly known as the “ague cake”. Although it is apt to fluctuate in size it is most certainly always swollen during an acute attack. On section the surface is dark, at times almost black, dark-red, purple or chocolate color from congestion and melanin pigmentation. In severe subtertian infections, the parenchyma may be so softened as to be almost diffluent and so swollen that the capsule is tightly stretched. When the pulp is washed, the malpighian bodies stand out as gray particles.

In chronic cases perisplenitis develops from stretching or tearing of the capsule, so that rupture may occur spontaneously or as the result of violence. On microscopic examination the organ contains a large number of macrophage cells, the special cells of Billroth, fibrinous cords, and sinus-lining littoral cells. In the chronic stage there is replacement by fibrous tissue. The malpighian bodies shrink while the pigment becomes scattered. All erythrocytic stages of the parasites can be detected in the red cells (P. vivax or P. falciparum) as well as the merozoites set free in the pulp. Numerically they are more numerous than in any other organ.

Malaria pigment is readily recognized free within the tissue spaces and enclosed within the reticulo-endothelium, and especially in the mononuclear cells. In acute cases the reticulo-endothelial system becomes blocked with pigment and in the later stages this is also replaced by fibrous tissue. Areas of thrombosis and hemorrhagic necrosis also occur.

The liver is usually congested, enlarged, pigmented, and olive-brown in color, especially in the left lobe which receives the splenic blood. Glisson’s capsule which surrounds the portal system is thickened and stretched. In chronic malaria there is fibrosis and round-cell infiltration which originates, it is thought, from the cryptozoic or tissue stages of the parasites. In infancy and early childhood, the enlargement, is mainly due to sinusoidal dilatation; in later years, the congestion is mainly confined to the center of the lobule, and so the appearance resembles that, of the “nutmeg” liver of heart failure. The slaty gray color frequently encountered is due to deposits of pigment. Parasitized erythrocytes and melanin (hemozoin) pigment are found within Kupffer cells.

Electron micrograph of plasmodium travelling through the cell

It is probable that the slight periportal fibrosis which is commonly encountered in African livers has a dual pathology because, in addition to malaria, there is malnutrition which is responsible for diffuse, piecemeal necrosis of the hepatic cells. Parasites, in all erythrocytic stages, are found in the sinusoids and in the parasitized erythrocytes. The parenchyma, cells do not usually take up malaria pigment, but contain granules of hemosiderin. Lysis of the red cells leads to obstruction and over-distension of the bile canaliculi which become obstructed by bile pigment. The parenchyma cells show all stage of degeneration, and in severe P. falciparum infections there is widespread focal necrosis surrounding the central vein. Small hemorrhagic areas may also be present.

Malaria pigment is now termed hemozoin, and is a compound of hematin which contains non-ionizable iron; hemosiderin also does so but it does not give the Prussian blue reaction with potassium ferrocyanide, unless first acted upon by nitric acid and hydrogen peroxide. In the kidneys, it is to be noted that albuminuria is common in malaria and may adumbrate serious renal damage, and this is specially true in subtertian and quartan infections. Sometimes there is azotemia with hyperpiesia and cardiac hypertrophy. In severe cases the lumen of the tubules becomes filled with granular casts and the cells show fatty changes resembling parenchymatous degeneration. Signs of glomerulonephritis are also sometimes present. In quartaephrosis Surbek (1931) occasionally found the enlarged, pale, white kidneys typical of degenerative parenchymatous nephrosis.

The changes in the heart in subtertian malaria are edema due to cardiovascular failure. In the bone marrow the yellow and adipose tissues are very vascular. The red marrow is of a chocolate brown, especially at the periphery and this is due to deposits of pigment. Phagocytosis is evident with hemozoin, macrophages and parasitized cells in large numbers. In chronic cases the reticulo-endothelium is hypertrophied. In the marrow itself there is a normoblastic response. Occasionally megaloblasts may be seen and reticulocytes are increased in the peripheral blood.

In the pancreas there is often focal necrosis, affecting the nutrient vessels of the Islets of Langerhans. Rarely the pancreas is hemorrhagic. The suprarenals are attacked in subtertian malaria, resulting in partial or complete loss of lipoids in the cortex, with congestion and blockage of vessels with malaria parasites; this is probably responsible for algid symptoms in subterian malaria. In the placenta the . maternal sinuses are packed with parasites interfering with the nutrition of the fetus, which may become infected at birth, possibly through the umbilical cord, or through a tear in the placenta. In the intestinal tract achlorhydria is common in I acute stages. The blood capillaries are loaded with parasites and degeneration of the mucosa is encountered which may give rise to dysenteric symptoms in life.

The brain usually bears a leaden hue due to deposition of hemozoin and the presence of parasitized cells in the capillaries. The gray matter is smoky gray while the white matter is speckled with punctiform hemorrhages (cerebral purpura). The smaller capillaries become completely blocked with parasitized cells and the plugging is most common at the bifurcation of the blood vessels (Ariete).

Malarial granulomata are focal degenerations in the brain substance, the result of former hemorrhages. Granuloma is sometimes an inappropriate term, for these lesions somewhat resemble tubercles and are formed by an agglomeration of glial cells around a focus of degeneration.

In massive infection the capillaries are blocked and thrombosed. As Maegraith has pointed out, thrombosis takes place. There are numerous small hemorrhages with “granulomata” in the subcortical zones. Clinically this is associated with malarial coma. Generalized toxemia is characterized by fits and convulsions. There are small and scattered hemorrhages. Embolism produces punctiform hemorrhages, especially in the corpus callosum.

Clinical manifestations

An attack of malaria may either be a primary attack or a relapse. A primary attack normally develops after an incubation period of 10-14 days; by direct blood inoculation it is about 11 days. In insect transmitted subtertian malaria, where the number of infecting bites is high, the incubation period tends to be shorter and may only be five days. Iaturally transmitted benign tertian malaria, especially in Europe, there may be latent period of several months before symptoms appear; the latent period usually covers the winter months. P. ovale may also show very long latent periods (Trager and Most, 1963). This is known as latent malaria. The latent period preceding the primary attack is known as incubation latency; a period or periods following upon the primary attack are know as infection latency. In subtertian malaria there is no latency in the same sense as in benign tertian. The type of temperature curve, whether intermittent or remittent, is less significant than formerly considered to be the case. Thus primary benign tertian infections may produce a remittent temperature curve before assuming the classical intermittent character. Two or more generations of tertian parasites, maturing in the blood at different times, will produce quotidian fever and two or more generations of quartan will give a fever on two successive days—quartana duplex—or conversely on three successive days, a quotidian fever—quartana triplex.

Relapses are defined as recurrences of malarious symptoms and the reappearance of malaria parasites in the peripheral blood, following recovery from the initial attack. Therefore relapses must be distinguished from reinfections.

Recrudescences of malaria are defined as relapses of the patient at the time he is removed from the endemic area. Relapses often follow the cessation of suppressive treatment, exposure to cold, exertion, parturition, or surgical operations.

The characteristic ague is divided into three stages : (1) cold stage, (2) hot stage and (3) sweating stage. One or even all these stages may be absent on occasions, especially when the infection is of long standing, whilst in subtertian fever many symptoms are so bizarre that they may be most misleading, so as to enforce the conviction that in many respects it is quite a different disease.

Herpes on lips and nose (fever sores), often extensive, frequently follow the rigors and are an accompaniment of all forms of malaria. Similar eruptions have beeoted on the ears.

 

Premonitory stage.—For several days before the actual attack the patient may be conscious of headache, lassitude, a desire to stretch or yawn, aching in the bones, anorexia, sometimes vomiting.

Cold stage.—This usually lasts one to two hours, and is the rigor, or “ague.” The feeling of cold is intense and universal. The teeth chatter; – the patient shivers from head to foot and wraps himself up in any garment he can lay his hands upon. Vomiting may be most distressing. The features are pinched, the fingers shrivelled and the skin blue like “goose-skin” (cutis anserina). The feeling of cold is purely subjective, because the temperature is rapidly rising. Children usually have convulsive fits.

Hot stage.—The hot stage may last from three to four hours. The shivering abates and gives place to, or alternates with, sensations of great heat. The clothes are thrown off. The face is flushed ; pulse full, bounding and usually dicrotic; headache intense ; vomiting usual; respiration hurried ; skin dry and burning; the temperature rising to 40° C, sometimes 41,1° C, rarely higher.

Sweating stage.—This usually lasts from two to four hours. The patient breaks out into profuse perspiration with sweat literally running off him in streams, saturating clothes and bedding.   With sweating the fever rapidly declines. Headache, thirst and distress give place to a feeling of relief and tranquillity. When it has ceased the patient may feel exhausted, but quite well and able to go about. The body temperature is now subnormal and remains so until the approach of the next paroxysm, one or two days later. The total duration of the fever cycle may be from six to ten hours.

Urine and feces in ague.—During the cold stage the urine is abundant and limpid, and micturition frequent; during the hot sweating stages it is scanty, cloudy, sometimes albuminous. Urea excretion is increased during the rigor and hot stages, and so is that of the chlorides and sulphates. Phosphates, on the contrary, diminished during the rigor and hot stages, are increased during defervescence. Augmentation in urea excretion commences several hours before the attack, attains its maximum towards the end of the rigor, and decreases during the terminal stages, though still above the normal figure.

A fleeting glycosuria has also been observed from time to time. The urine usually contains urobilinogen and urobilin in excess during the attack, but they decline with the temperature and form a valuable diagnostic sign, especially in subtertian malaria. The corresponding pigment in the feces (hydrobilirubin) is increased twenty times the normal amount whilst parasites persist in the blood.

The spleen during ague.—The spleen is enlarged and painful during the rigor, but in early infections is not always palpable, a feature which became specially noticeable in the second World War in India, Burma, and New Guinea, in benign as well as in subtertian infections. At first, the enlargement recedes during remission, but later, when relapses and reinfections occur, it becomes permanent as in the “ague cake.” In primary infections the spleen is soft and spongy and therefore difficult to palpate, but in subsequent relapses it becomes harder and more fibrous. Spontaneous rupture of the spleen has been reported more frequently in P. vivax infections them with other species. Usually it is the result of violence, but Bearn (1961) has shown that in an adherent spleen it may be due to extensive subcapsular hematoma. Successful splenectomy does not necessarily extirpate the malarial infection.

Period of the day at which ague commences.—Quite a large proportion of agues “come off” between midnight and noon or in the early afternoon. This time factor may constitute an important point in diagnosis, especially as pyrexial attacks somewhat simulating malarial agues may be caused by liver abscess, tuberculosis, Escherichia coli infections of the urinary tract and septic conditions, in all of which febrile recurrences are apt to take place during the afternoons or evenings.

Course of benign tertian and quartan fevers.—Benign tertian ague usually lasts ten hours or less and may be taken as the type of a malarial attack. In some cases the rise of fever is rapid and high, and the temperature may reach 40,6° to 41,1 °C within an hour or so; on the other hand, in some cases none of the clinical phenomena are present and the temperature does not rise above 37,2°-37,8 °C. Benign tertian, unless complicated, is not usually fatal; but the persistent and relapsing character makes it a tiresome disease and, if prolonged, it may produce severe anemia and debility. It may also produce thrombocytopenia.

In Central Russia, a fulminating type of benign tertian malaria, with hyperplasia of the spleen and cerebral edema, especially in children, has been described. Also two types (Nikolaev, 1935) are recognized: the Northern with an incubation period of 8-14 months; the Southern with an incubation period of 9-21 days. The length of this period does not depend upon the number of sporozoites introduced. Different incubation periods are actually produced by mosquito bites of the same batch after feeding on the same donor (Tiburskaya, 1961).

Certainly many strains of P. vivax seem to exist which differ in their virulence; some are mild, as in Holland; sometimes the fever is trivial and isolated attacks, without recurrence, are common enough. Various strains of P. vivax have been found to possess distinctive characters and vary in the number and frequency of the relapses they produce.

The presence of a rigor appears to be an index of severity. The mean maximum temperature for the paroxysms is 40,1 °C. As a general rule, the duration of a simple benign tertian infection before the parasites die out from the peripheral blood is nine months to one year after leaving the endemic area, but exceptions to this rule occur, as clinical relapses, with parasites in the blood, have been recorded as long as three years after the original infection. As it is seldom fatal, the pathology is not so well known as that of subtertian malaria, but it resembles it in a minor degree.

The fever in quartan malaria is generally smart while it lasts, and is well defined in its various stages, but it does not produce much systemic disturbance or cachexia or rigors. It has often been remarked that, whilst individual attacks of this infection are amenable to quinine and atebrin, the disease is more persistent than tertian or subtertian, so that attacks are apt to occur from time to time over a period of many years and may persist as long as 12-21 (Duggan and Shute, 1961). It is becoming increasingly realized that sometimes quartan parasites may be present in the blood without evoking any special symptoms. Parasites are usually scarce in the peripheral blood. They are more resistant to antimalarial drugs in the sense that they persist in the bloodstream for a week or more while the patient is taking the drug.

Quartan periodicity is the hall-mark of quartan malaria and is hardly ever found in any other disease. Double quartan and triple quartan fevers may be observed. In the latter the temperature course becomes quotidian. Occasionally, quartan fevers are encountered without splenomegaly and apparently when parasites can be found in the blood only after prolonged search: sometimes not at all, so that their true nature can be ascertained solely by the action of chloroquine by injection.

Relapses in quartan malaria may be of two forms: those occurring after a short interval are due to exacerbation of a low-grade parasitemia, but those in the longer interval of several months to release of exoerythrocyte parasites from the liver into the bloodstream.

Coma.—Sometimes the patient, without hyperpyrexia (the temperature perhaps not rising above, or even up to, 40°), may lapse into coma. The coma may pass away with a crisis of sweating ; on the other hand, an asthenic condition may set in and death supervene. There is often a paralytic squint, extensor plantar response and Cheyne-Stokes respiration. When subcortical hemorrhages are present, death usually ensues. There is a marked increasing of pressure in the cerebrospinal fluid, with increasing of lymphocytes up to 400 per mm, as well as of albumin and globulin. Occasionally, granules of malarial pigment may be found. It is important to note that parasites may be very scanty in the peripheral blood and not infrequently they may be absent altogether. The coma may persist for as long as 46 hours and then recovery ensue with quinine injections (chloroquine) as in the case reported by A. Cr. Tresidder in 1914.

Other cerebral manifestations are cerebral depression, excitation, cerebellar ataxia (Sawyer-Brown variety), behavior changes and character alterations, meningismus closely simulating meningitis. Rarely a focal spine lesion may cause paraplegia.

Algid forms. The algid forms of pernicious attack, as indicated by the name, are characterized by collapse, extreme coldness of the surface of the body or, in other words, by peripheral vascular failure. These symptoms usually co-exist with elevated axillary and rectal temperature. Flooding of the peripheral blood with vast numbers of parasites in all stages of development gametocytes as well as schizonts sometimes found. The prognosis is usually bad, but rarely this may be seen in an attack of average severity. It indicates a continuous fever of at least two weeks, or a relapse of short duration.

There are some misleading clinical forms of subtertian malaria which are important, for instance the gastric, choleraic, dysenteric, hemorrhagic, and edematous forms. The last with generalized anasarca were prevalent in war refugees from Givece (1945) and in the great Ceylon epidemic of 1934.  Acute hemolitic anaemia, resembling pernicious anemia, may be a prominent of subtertian malarial cachexia. More rarely seen are the edematous forms with anasarca and ascites and also with nephritic signs with blood cells and albumin in the urine.

Diagnosis from clinical signs. The most important clinical sign is periodicity of the fever, which occurs in its most typical form in the tertian and quartan infections; in the subtertian, however, fever may be most irregular, or there may be no pyrexia at all.

Enlargement of the spleen is a common clinical sign in all forms of malaria. In old-standing infections it may be very large indeed, and occupy the greater part of the abdominal cavity, but in early, and it may be very severe, cases it may not be sensibly enlarged at all, and therefore fails entirely as a clinical guide; usually, however, in the absence of splenic enlargement, splenic pain is present during the attack. Moreover, the patient may be suffering from some totally different disease, and the palpable spleen may be the result of a long-standing malaria infection, quite unconnected with the attack in question.

To the clinician accustomed to many cases, the general appearance of malaria patients, the bright glistening eye, set in rather a dusky orbit, contrasted with the pale and ochreous complexion, combine to create an almost diagnostic appearance. Amber colored urine due to excessive urobilinuria. especially in subtertian malaria, and even in the absence of parasites in the peripheral blood, may be suggestive.

Sudden fever in a previously healthy person who has recently arrived from a malarious country usually turns out to be malaria. The patient will generally give a history of similar attacks while resident abroad, but there are exceptions to this rule, for, occasionally, residents of tropical countries may develop their first attack of malaria shortly after arriving in a cold climate, and this attack, aggravated by the conditions, may run a very severe course; this is especially the case with recent arrivals from the west coast of Africa, and it is true for both benign tertian and subtertian infections, the parasite lying dormant in the blood-stream perhaps as long as eight months; in the benign form a year or more. It should be borne in mind that, in the case of P. vivax, P. malarias and P. ovale all “prophylactic” drugs are in reality only suppressive. A possible diagnosis of malaria should therefore not be discounted on the grounds that drugs were continued for the advised 14 days after return to a non-malarious country.

An actual description of the febrile attack itself may be suggestive. The rapid rise of temperature, the history of the cold, the hot, and the sweating stages, the rapid defervescence of the fever, and the subsequent sense of well-being, are more characteristic of a malarial attack than of any other febrile disease. At times periodicity is a trustworthy enough clinical test. Tertian and quartan periodicity usually occur only in malarial disease, but have been seen in meningococcal septicaemia.

 

Differential diagnosis of malaria

http://emedicine.medscape.com/article/221134-differential

The differential diagnosis of malaria entails a knowledge of all fevers, both tropical and non-tropical.

The following are often mistaken for malarial fever cerebrospinal meningitis; fever of urinary origin (sometimes renal calculus); the fever attending the passage of gall-stones, or inflammation of the gall-bladder; that associated with pyelitis and surgical kidney; perirenal abscess; amoebic hepatitis and amoebic abscess of liver; lymphangitis, particularly that form associated with elephantiasis and other filarial diseases; undulant fever, relapsing fever; trypanosomiasis; kala-azar; “short-term fevers” of which dengue and sandfly fever are the most typical; the fever associated with tuberculous disease, with ulcerative endocarditis, with some types of pernicious anemia, with splenic leucocythemia, with visceral syphilis, with pulmonary carcinoma, with rapidly growing sarcoma, with forms of hysteria, and with many obscure and ill-defined conditions.

Treatment

At cupping of fever attacks at any kind of a malaria use preparations with shizotropic action: Chingamin (or.: Delagil, Hlorohin, Nivachin, Resochin, Trochin), and also quinine sulfas, quinine Dichlorid, Hydroxyhlorin (Plaquenil), Chloridin (Pyrimethamin, Tindurin), Sulfanilamid preparations, Meflohin, Tetracyclin, Doxycyclin. These preparations are active against bloody shizontes. The greatest action has Chingamin. Concerning tissue forms of plasmodiums the most active is Primachin.

At acute disorders of disease use Chingamin diphosfat during 3 days more often: in 1 day 1,5 gm (at once 1 gm and in 6 hours the others 0,5 gm), in 2 nd and 3-rd day – unitary  0,5gm. The serious form of a tropical malaria demands prolongation of treatment course by Chingamin  2 days 0,5 gm 1 time in days If plasmodiums are refractory to Chingamin, indicate quinine Dichlorid  2 ml  50 % of solution 2 times in 6 – 8 hours or in a vein very slowly  1 ml in 20 ml. 40 % solution of glucose, and then two injections under skin  1 ml. 50 % of solution. Chloridin in combination with Sulfanilamides preparations of prolonged action or the combined preparation Fansidar, which contains 0,5 gm of Sulfadoxin  and 0,025 gm of Chloridin:  3 tablets unitary. Fansidar may be given also for prophylaxis of relapse of tropical malaria.

The mentioned preparations provide complete convalescence at tropical malaria.  In case of tetrian fever and oval malaria indicate Primachin  which have action upon tissue shizontes and prevent appearance of recedives. Similar activity have also Tetracyclin. Primachin is indicated simultaneously with Chingamin or right after terminations of treatment by it.

Treatment of specific complications is carried out in the urgent order. At development of malarial coma use a solution of quinine Dihydrochlorid. The next days indicate the preparations per os. Simultaneously carry out desintoxication therapy with Reopolyglycin, Polyglucin, Albumin, Rheogluman, Polyionic solutions. The total quantity of infused liquid should not exceed 1500 ml. Infuse up to 150 mg of Prednisolon in vein. Among other agents Diprazin, Suprastin, Furosemid are indicated.

At hemohlobinurine fever treatment starts with an immediate cancellation of Quinine, Primachin, Sulfanilamide preparations which might cause this complication. Infuse Cordiamin, Corglykon or Strophanthin, Phenylephin hydrochlorid, Prednisolon, and also Reopolyglycin, Quartasol or another polyionic solutions. In case of development of serious anemia transfuse the blood of the same group, blood plasma.

Individual chemioprofilaxis is carried out for the persons leaving in the endemic regions. For this purpose use Chingamin  0,5 gm once a week, and in hyperendemic regions – 2 times per one week. Preparation is indicated during 5 days before arrival, all period of stay and during 8 weeks after departure. Among local population chemioprofilaxis begin 1 – 2 weeks before occurrence of mosquitoes. Occurrence of the tropical malaria is caused by drug resistant plasmodiums, prevent by reception of Fansidar once a week. To the persons who have arrived from endemic center of a tetrian fever, seasonal prophylaxis of relapses by Primachin in tablets  0,027 gm per day during 2 weeks is carried out.

Leptospirosis

http://www.medicinenet.com/leptospirosis/article.htm

Leptospirosis is an acute generalized infectious disease, characterized by extensive vasculitis, caused by spirochetes of the genus Leptospira. It is primarily a disease of wild and domestic mammals; humans are infected only through direct or indirect contact with animals.

Leptospira

 

Pathogenesis

The pathogenesis of leptospirosis is characterized by changing several phases. The first phase includes the pathogen penetration and a short-time primary leptospiremia. The leptospiras penetrate the human organism through the skin of the mucous membranes, travel along the lymph tracts, penetrate the blood and then various organs – the liver, kidneys, adrenal glands, spleen, lungs and others. This phase lasts 7-20 days, it corresponds to the incubate period.

The second phase includes secondary leptospiremia, it coincides with the beginning of the clinical manifestations of the disease, the generalization of the process. The leptospiras penetrate the organs and tissues with the blood flow again, fix on the cell surface (especially, in the kidneys, liver, adrenal glands), can overcome the hametoencephalic barrier. The leptospiras do not cause a destruction and they do not parasites intracutaneously. They stick to the cell surface, can stay in the inter-cell space.

The third phase is a phase of toxinemia that is accompanied by an expressed fever. The most important pathogenic factor of this phase is capillary toxicosis. The rupture of the capillary endothelium results in the diapedesious hemorrhages into various organs and tissues. It is clinically manifested as a hemorrhagic syndrome. Thrombocytopenia plays a part in the origin of the hemorrhagic syndrome, it is connected with the influence of the leptospira lipase on the phospholipids of thrombocytes membranes and their gluing together with the formation of the primary thrombocytous congestion. The vessels of the liver, kidneys, adrenal glands get affected most of all, there may develop Waterhause – Friedrichen syndrome. The degenerative and partially necrotic changes of the liver parenchyma as well as hemolysis oferythrocytes under the affection of hemolysins are the cause of jaundice which has a mixed character.

Leptospira in a liver

The influence of leptospiras and their metabolites on the cellular wall results in the affection of the adrenal gland epithelium, all the cortical and subcortical layer of the kidney that results in the uropoiesis affection. There is a possibility of the development of renal insufficiency.

The fifth phase includes the formation of the sterile immunity. The tense humoral immunity is combined with the expressed local organic and cellular immunity. Then comes a stable recovery.

Pathological anatomy

Leptospirosis is characterized by the affection of the capillary endothelium of a various organs and tissues. The walls of the vessels are fragile, their permeability is increased, this is accompanied with numerous hemorrhages in the kidneys, liver, lungs, endocardium and pericardium, mucous membrane of the gastroenteral tract. The liver is enlarged, plethoric and with smooth surface.

The histological investigation shows an edema of the interstitial tissue, dystrophy of the hepatic cells without an expressed cytoptesis of hepatocytes, biliary thromboses in the central zone of the lobules.

The most considerable changes can be found in the kidneys. The kidneys are considerably enlarged, there are such typical symptoms as a stroma edema, numerous hemorrhages, a sharply expressed granular degeneration of the convoluted tubules epithelium up to necrosis. The kidney affection in leptospirosis can be considered as nephrosonephritis.

There are hemorrhages in the adrenal glands, sometimes considerable. The muscle affection is also characteristic of leptospirosis, especially the affection of musculus gastrocnemius and musculus thoracic. There are hemorrhages of various sizes; an uneven swelling of the fibers, degenerative changes in the synapses of the muscular fiber and nerve, sometimes coagulatioecrosis which causes myalgia.

Dystrophy and lipid dystrophy develops in the heart muscle, sometimes there is interstitial myocarditis. There are hemorrhages in the lungs as well as in other organs. There is often an edema of the meninx vasculosas.

Clinical manifestations

The course of leptospirosis can be mild, middle-moderate and severe. The severity of the course depends on the microbe virulence, the dose of infection, the reactivity of the microorganism.

The main criteria of the severity are follows: the degree of toxicity, the expressiveness of the affection of the liver, kidneys, central nervous system, heart, adrenal glands, hemorrhagic manifestations.

There are cycles in the leptospirosis course. There is and incubate period, the beginning, height and convalescence.

The incubation period lasts 2-20 days (more often 7-10 days). The disease has an acute onset. The patient can indicate not only to the date but even the hour of the disease onset. The fever usually has a remitting or constant character, it lasts 5-9 days then it falls down in the form of accelerated lysis. There can be another wave (a relapse).

From the first hours the patients complain of intense headaches, pain in the muscles, especially, musculus gastrocnemius, the muscles of the scalp, neck, back and abdomen. In 1888 W. P. Vasiliev wrote that there is no such an intensive myalgia in the musculus gastrocnemius in case of any other disease. The abdomen pain can be so intense that there is a suggestion about an acute surgical pathology.

The symptoms of toxicity increase. The patients are flaccid, adynamic. The patients has a characteristic appearance – face is edemic, hyperemic, vessels of the scleras are injected.

There is often herpetic rash on the lips. In some patients (in 30 % cases) a polymorphic symmetric rash which stays for several days appears on the third – fifth day of the disease.

In some cases there is an enlargement and painfulness of the peripheral lymph nodes. The liver gets enlarged early, on the second-third day of the disease. Jaundice develops in the moderate severe – course as well as in the severe course. The liver has a dense consistence, it is painful at palpation. In a half of the patients the spleen gets enlarged.

There are considerable changes in the cardiovascular system: dull heart sounds, sometime relative bradycardia, arrhythmia, extrasystole. In case of an expressed toxicity the arterial pressure sharply decreases (up to collapse) as a result of a decrease of the precapilary arteries.

The initial period of leptospirosis is characterized by the peculiar changes in the central nervous system, in some patients there are such symptoms as disorders of the consciousness and even unconsciousness, cramps besides an expressed persistent headache, insomnia, delirium. In 10-40 % cases there are meningeal symptoms: rigidity of the occipital muscles, Kernig’s sign, Brudzinsky’s sign that are distinctly manifested on the fifth-eighth day of the disease. In such patients the spinal puncture confirms the diagnosis of serous leptospirous meningitis – cerebrospinal fluid flows out under an increased pressure, it is transparent. The microscopia of the cerebrospinal fluid shows leptospiras, during the regular one outside the dark field of vision – moderate lymphocytic pleocytosis. The amount of protein is increased. Leptospirous meningitis usually has a nonmalignant character, it usually lasts 8-10 days.

At the end of the first week, and sometimes earlier jaundice develops in some patients (12-20 %). The intensity of jaundice and its duration depends on the severity of the disease and can last several weeks (1-4). A moderate skin itching is quite possible. The urine is dark, the color of the excrements is not changed.

With the development of jaundice the condition of the patients usually worsens. The most severe manifestations of leptospirosis appear at the end of the first week – at the beginning of the second week of the disease.

The hemorrhagic syndrome appears on the seventh-tenth day: petechial eruption on skin, hemorrhages under the conjunctive, hemorrhages in the nose, gums, stomach, intestine, uterus. The hemorrhages can be repeated, massive and result in anemia. Many clinicians have observed that the expressiveness of the hemorrhagic syndrome corresponds the severity of leptospirosis and has a certain prognostic significance. The degree of the kidneys affection is even more significant while evaluating the severity of leptospirosis, the kidneys are always affected to some degree in leptospirosis.

Patients with leptospirosis

 

From the first days of the disease there can be oliguria, moderate proteinuria, in the urine there are fresh erythrocytes, leukocytes as well as hyaline casts and the cells of the renal epithelium. The symptom of the kidneys affection become the most expressed from the seventh-tenth day of the disease. Oliguria can be followed by anuria, an acute renal insufficiency may develop, m spite of the development of an acute renal insufficiency, there is usually no edema and arterial hypertonia in leptospirosis. Sometimes an acute renal insufficiency develops very early, on the fourth day of the disease. It is an acute renal insufficiency resulting in uremia that is a frequent cause of the lethal outcome of the disease. If the therapy is timely and adequate, the kidneys affection in leptospirosis can be cured. Oliguria is followed by polyuria, and function of the kidneys gets gradually normalized.

The second week corresponds to the severity of disease. At this time jaundice becomes the most intensive, the hemorrhagic and meningeal syndromes increase or appear for the first time. The changes in the cardiovascular system increase: the pulse is rapid and weak, a systolic murmur is sounded in the apex cordis, there can be extrasystolia. The electrocardiogram shows diffusive changes of the myocardium.

At this period of the disease the infiltrates connected with the hemorrhagic foci are sometimes formed in lungs, this is accompanied by the sanguinolent sputum secretion.

By the end of the second week the condition of the patients improves. The headache and myalgia reduce, the jaundice intensity gradually decreases, a great amount of urine begins to excrete. The patients feel weak for a long period. The duration of the disease averages to 3-4 weeks. Some patients (20-60 %) may have relapses. In 5-7 days after the feverish period the temperature rises again, headaches and myalgia appear. The relapses and acute forms are not so severe as the first phase, as a rule. The temperature does not usually rises very high, the fever does not last more than 2-3 days. Some patients have 3-4 acute forms of relapses.

In leptospirosis the hemogram is characterized by the progressive anemia, a low reticulocytes number. In the patients with a hemorrhagic syndrome there is expressed thrombocytopenia, an increased period of the blood coagulability. Leukocytosis is a characteristic feature. The number of leukocytes increases up to 12-25×10⁵ in 1 mkL. In the differential blood count there is neutrophilia with a shift to the left, expressed lymphopenia. The ESR reaches 40-60 mm/h.

The bilirubin amount in blood increases in case of the icteric form. The level of prothrombin may moderately decrease. The activity of transaminases is either normal or slightly increased on the tenth-fifteenth day of the disease.

The asthenovegetative syndrome is a characteristic feature of the convalescence period. Anemia and proteinuria remain for a long time.

Some patients have eye affections – uveitis, iritis, iridocvclitis that develop in 2 weeks and in several months after the onset of the disease. There can be other complications in the acute period – massive hemorrhages, an acute renal and hepatic insufficiency, uremia, myocarditis, an acute cardiovascular insufficiency.

 

Diagnosis

It is quite difficult to diagnose leptospirosis, especially during the first days of the disease. The bacteriological method is of a little practical importance because leptospiras grow badly and slowly on the artificial media. The correctly taken epidemiological history plays the most important part in diagnosing leptospirosis. It is necessary to take into account the patient’s occupation, his contact with agricultural animals, work in the meadows, swimming in the rivers and ponds, the existence of rodents in the surroundings. The epidemiological history not only determines the direction of diagnosis but gives an opportunity to control the environment. The following peculiarities of the clinical symptoms are taken into consideration: jaundice, accompanied by fever, myalgia, hematuria, hemorrhages. The diagnosis based on the clinical-epidemiological investigation, is confirmed by the laboratory data.

The materials used for diagnosing leptospirosis are blood, urine, cerebrospinal fluid.

The following methods of the laboratory diagnosis are used:

1. Bacteriological, bacterioscopic.

2. Serologic.

3. Biologic.

The bacteriologic investigation includes the primary microscopia of the initial material and its inoculation of media for acquiring the leptospira clean culture. The patient’s blood serum, cerebrospinal fluid or urine are centrifuged. The fall out is investigated with microscope in a dark floor. Leptospiras are found as thin sinous mobile threads that look grayish -whitish on the dark background. That is necessary to note that the presence of leptospiras in blood is undoubtedly indicative of leptospirosis, but the negative result does not allow us to exclude the disease. The initial material inoculation of the water-serum medium consists of the native rabbit serum. The inoculation is incubated for 30 days at a temperature of 28-30 °C, the inoculation is examined on the dark floor of the microscope every 5-7 days.

The serologic investigations are done in the dynamics of the disease including the convalescence period. The reaction of the microscopic agglutination and lysis, as well as the complement fixation reaction are used to find antibodies in the serum of the sick people.

The reaction of the microscopic agglutination and lysis are done by a drop method with various serums of the patient’s blood and with those leptospira serotypes which can be found hi this area. The results of the reaction are taken into account with the help of a microscope with a dark floor. In the positive case there are phenomena of sticking together, the leptospira agglomeration in form of small “spiders” and different degrees of their lysis. The titer is considered to be diagnostic when the serum is diluted 1:50 -1:100.

The specific antibodies are discovered in the patient’s serum at the end of the first – the beginning of the second week of the disease. The antibodies can remain in patients for several years, that is why the investigation of the twin serums are of a great diagnostic importance.

Leptospiras appear in liquor later than in the blood, that is why its investigation (microscopia and inoculation of the same media as the blood) are done when there are symptoms of meningitis. Urine can be investigated from the first day to 3 months from the disease onset.

The guinea-pigs that are very sensitive to L. icterochaemorrahaigae are used as a model for the biological test. The animals are infected by injecting the infected material (blood, urine, cerebrospinal fluid taken sterile from the sick person) intraperitoneally, intracutaneously, intravenously, through the scarified skm and mucous membranes. The material is taken at the time when the bacteriological and bacterioscopic investigations are done. The animals die if there are leptospiras in the initial material.

Differential diagnosis

However, in some cases there are diagnostic difficulties because of the polymorphism of the clinical picture, separate symptoms of which make it difficult to diagnose a disease (jaundice, fever, abdomen pain, myalgia, meningeal syndrome).

First of all it is required to differentiate the disease from flue, typhoid fever, hemorrhagic fever with a renal syndrome (HFRS), virus hepatitis, meningitis.

In case of flue the headache has a distinct location (in the superciliary arch area), there is no hepatosplenomegaly, jaundice. There are expressed catarrhal symptoms. The hemogram shows leukopenia, neutropenia, the ESR is usually normal. The fever last from 2-3 to 5 days.

If there are such symptoms as an acute onset of the disease, a high temperature, intense headaches, the appearance of the patients, the liver and spleen enlargement, it is necessary to differentiate leptospirosis from typhoid fever. However, the following symptoms are characteristic of the initial period of typhoid fever: Kiari-Avtcin’s sign, Govorov-Godolie’s sign, Rozenberg’s sign, and early increase of the spleen. There appears massive roseole-petechial eruption on the side surfaces of the breast, abdomen, extension surface of the extremities.

In HFRS there are no pains in the musculus gastrocnemius, there are such characteristic symptoms as loin pains, Pasterntsky’s positive sign, petechial eruption located in the area of the shoulders and armpits. There is prolonged hypoisosthenuria, and in the urine fall out there are waxy casts, degenerative cells of the renal epithelium besides erythrocytes, hyaline casts. There is no jaundice and meningeal syndrome. The hemogram shows leukopenia at the increased ESR at the onset of the disease.

Virus hepatitis has a gradual onset, without chills, the temperature rises at the pre-icteric period. Muscle pains, scleritis, conjunctivitis are not characteristic of it. There are no meningeal and renal syndromes. The activity of transaminases is considerably increased. The hemogram shows leukopenia, low ESR.

If it is necessary to differentiate leptospirous meningitis form serous meningitis of another etiology, it is necessary to take into account the epidemiological history, pain in the musclus gastrocnemius; the development of the meningeal syndrome in 4-6 days after the disease onset, the simultaneous affection of the liver, kidneys; a hemorrhagic syndrome.

 

Treatment

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Among the most effective etiotropic agent there is combination of antibiotics and antileptospirosis  immunoglobulin if they are indicated in an initial stage when Leptospires are in blood. Benzylpenicillin, Tetracyclin, Erythromicin and Streptomycin are indicated more often. The daily dose of Benzylpenicillin can be changed from 3 to 12 millions UN, however, the dose 6 – 8 millions UN is more often indicated per day (in a muscle). It dosage depends on gravity of the disease current. The maximal dose of a preparation is indicated at development of  meningitis. Ampicillin, Oxacillin, Ampiox are effective semisynthetic Penicillins. Benzylpenicillin or semisyntetic analogue can be combined with Streptomycin. Tetracyclin is indicated  0.2-0.3 gm 4 times per day, it less often, than Penicillins, causes reaction such as Yarish-Gersgeimer, however strengthens a permeability of vascular wall and promotes development of a hemorrhagic syndrome. It is contrindicated at the icteric form of leptospirosis fever and development of renal failure. Treatment with antibiotics is carried out during all feverish period and 2-3 days of normal temperature. In case of occurrence of relapse a new course of an antibiotic therapy must be indicated.

Clinical observations of last years has testified the inefficiency heterogeneous  antileptospirosis  immunoglobulin, oppression of immune system by it. The allogenic donor immunoglobulin which is effective in the first 3-5 days of disease are applied in medical practice, has no side-effects. The preparation prevents development of acute renal failure.

With the purpose of desintoxication and improvements of microcirculation in a vein there are infused  solution of  glucose, Reopolyglucin, Rheogluman, Trisol, Quartasol, and ascorbic acid. Good desintoxication effect have the preparations that neutralize ammonia: an Ornithine, Ornicetil, Glutargin. At severe intoxication Prednisolon and its analogues are indicated. The initial dose of Prednisolon is 60-120 mg and more, it is used for short course, quickly reducing dose in process of clinical improvement. Enterosorbtion with using of granulated coal SKN, Sillard P, Enterosgel, Polyphepan can be effective. At the icteric form there should be  prescribed diets № 5, 5A, and at pathology of kidneys – a diet № 7.

At the development of the  Disseminated Intravascular Coagulation (DIC) carry out a complex of medical actions according to hematological research. At I stage (hypercoagulation) infuse in a vein Heparin 2500 UN 4 times per day, Reopolyglycin, Dipiridamol (Curantyl), Pentoxyfilin (Trental) Contricali in bottles, ascorbic acid  5 %  solution in ampoules 1 mL: 5-10 mL 2 times per day. At II stages Heparin can be infused under the control of blood clotting time, other preparations (Reopolyglycin, Curantyl, Trental) – in the same doses, as at I stage of syndrome. At III stage of DIC infusing of Heparin is not indicated. At hypocoagulation there is indicated native plasma or Cryoprecipitat of plasma, trombocite mass. At hypofibrinolisis there are given acid aminocapronic, Contrical, Gordox, at secondary hyperfibrinolysis – synthetic antifibrinolitics, inhibitors of proteases – Streptokinasa, Fibrinolysin are indicated.

At the bleeding with a tamponade cold, and infuse Calcii chlorid, Vicasol, aminocapronic acid are used. Infusions  of a blood plasma, a red cells mass, Albumin are indicated at bleeding. If hepatonephric insufficiency develops simultaneously plasma transfusion of blood with infusion of erythrocytar and trombocytar mass 2-3 times, and are used instead of albuminous preparations, a mixture of amino acids, for example Alveosin-Neo is recommended.

 In occurrence of acute renal insufficiency (oliguria, hypoisosthenuria) there should be repeated lavages of stomach and an intestine 2-4 % solution of sodium hydrocarbonate, intravenous infusion of 40 % of glucose solution, Euphyllin, Mannit. At later infuse Furosemid (Lasix). At development of metabolic acidosis indicate Natrii hydrocarbonas and Tris-buffer. If medicamental therapy is not effective and oliguria stage lasts more than 3-4 days, there is a necessity in Plasmaferesis or Plasmasorbtion or Extracorporal dialysis by means of artificial kidney.

Prophylaxis

The deratization and sanitation veterinary measures the essential part of the prevention. Deratization is for decreasing of the activity of the natural foci (wild rodents control) and the sanitation of the anthropurgias foci (the sinanthropos rodents control).

One of the directions of leptospirosis prevention is the actions which break the transmission of the disease by water in the natural foci (mechanization of me agricultural work, the supplying of workers with water-proof clothes, a ban to swim in the infected reservoirs and to use unboiled water). Vaccination is recommended for the people who permanently stay in the natural foci. The people who belong to a group of high risk infection (cattle-breeders, veterinary doctors, the meat packing plant personal, night-men, deratizators) should be vaccinated with inactivated vaccine.