Tuberculosis reactivation

Infectious Tuberculosis reactivation, sepsis, opportunistic infections... 

Although anti-TNFa agents are well tolerated and have a good overall safety profile, pitfalls to the use of these drugs apparent with increasing clinical experience include infective complications and, in particular, reactivation of tuberculosis. To date, no statistically significant increased rate of tumour occurrence over that expected has been noted although cases of lymphoma have rarely been reported in patients treated with TNFa blockade. 

Reactivation of Latent Disease - Herpes Simplex Virus, Tuberculosis... 

Latent tuberculosis infection (LTBI) can lead to reactivation disease years after the primary infection occurred. 

These data show that for three psychotic disorders (schizophrenia, bipolar disorder and unipolar depression) the genetic contribution is over 50% but for reactive depression (in response to a traumatic life event ) and tuberculosis, an infectious disease caused by a species of Mycobacterium, environmental factors account for over 90% of the variance. 

Infliximab has been associated with infusion reactions, serum sickness, sepsis, and reactivation of latent tuberculosis. Adalimumab carries risks similar to infliximab. 

Turner J, Gonzalez-Juarro M, Ellis DL, Basaraba RJ, Kipnis A, Orme IM, et al In vivo IL-10 production reactivates chronic pulmonary tuberculosis in C57BL/6 mice. J Immunol 2002 169 6343-6351. 

Clinical improvement, especially the disappearance of fever or defervescence, is the best parameter to judge the response to therapy. However, clinical improvement can be difficult to monitor objectively in critically ill patients with multi-system disease. Also, clinical improvement can be very slow for certain infections, e.g. tuberculosis. The peripheral blood leukocyte count including the presence of early stages in leucocyte differention and the level of serum C-Reactive Protein (CRP, an acute phase protein) are parameters that can be sequentially determined to monitor improvement. For monitoring the effect of treatment of chronic infections such as endocarditis or osteomyelitis, weekly determination of the erythrocyte sedimentation rate has been proven useful. 

Serious adverse events occur in up to 6% of patients with anti-TNF therapy. The most important adverse effect of these drugs is infection due to suppression of the ThI inflammatory response. This may lead to serious infections such as bacterial sepsis, tuberculosis, invasive fungal organisms, reactivation of hepatitis B, listeriosis, and other opportunistic infections. Reactivation of latent tuberculosis, with dissemination, has occurred. Before administering anti-TNF therapy, all patients must undergo purified protein derivative (PPD) testing prophylactic therapy for tuberculosis is warranted for patients with positive test results. More common but usually less serious infections include upper respiratory infections (sinusitis, bronchitis, and pneumonia) and cellulitis. The risk of serious infections is increased markedly in patients taking concomitant corticosteroids. 

Anti-TNF antibodies, eg, infliximab, others Bind tumor necrosis factor and prevent it from binding to its receptors Suppression of several aspects of immune function, especially ThI lymphocytes Infliximab Moderately severe to severe Crohn s disease and ulcerative colitis others approved in Crohn s disease Infusion reactions reactivation of latent tuberculosis increased risk of dangerous systemic fungal and bacterial infections... 

IgGl molecule. Consequently, an artificial antibody is constituted with two Fab sites, which are soluble human 75-kDa TNF-a receptors. It competitively inhibits the binding of TNF molecules to the TNF receptor sites. The binding of etaner-cept to TNF renders the bound TNF biologically inactive, resulting in the reduction of the inflammatory activity. The most frequent adverse side effects are injection site reactions, infections and headache and malignancies are rare. Etanercept is not recommended for patients with serious infections or sepsis and does not appear to result in the reactivation of tuberculosis. 

The most important adverse effect of infliximab therapy is infection due to suppression of the THl inflammatory response. Reactivation of latent tuberculosis, with dissemination, has occurred. 

Ghiladi RA, Medzihradszky KF, Rusnak FM et al (2005) Correlation between isoniazid resistance and superoxide reactivity in Mycobacterium tuberculosis KatG. J Am Chem Soc 127 13428-13442... 

Infectious Opportunistic infection, upper respiratory tract and other infections, disseminated tuberculosis, hepatitis B reactivation... 

Varicella-zoster virus is a member of the Herpesviridae femily. The viral contagion is transmitted via aerosolized water droplets or close physical contact with infected lesions. The primary infection results in varicella or chickenpox. The varicella infection can have potentially devastating ocular sequelae the most common is anterior uveitis followed by SPK. After the primary infection, latent infection occurs in multiple ganglia throughout the body. Herpes zoster is the resultant reactivation of the latent varicella-zoster virus and most often occurs in elderly and immunocompromised patients. Factors such as physical and emotional trauma, immunosuppressive medications, irradiation, cancer, tuberculosis, malaria, and syphilis are known to reactivate the virus. 

The widespread use of isoniazid prophylaxis for tuberculosis has focused attention on the liver injury caused by this drug. About 20% of patients treated with isoniazid will show elevated blood concentrations of liver enzymes and bilirubin that subside as treatment is continued (25). However/ clinical hepatitis develops in some patientS/ and these reactions can prove fatal. Current understanding of the mechanism of isoniazid-induced hepatotoxicity is based on the metabolic pathways shown in Figure 16.6 (26/ 27). It has been demonstrated in an animal model that hepatotoxicity is correlated with plasma concentrations of hydrazine but not of acetylhydrazine or isoniazid (28)/ and that pretreatment with an amidase inhibitor can prevent toxicity (27). However/ it is postulated that hydrazine is further metabolized to a chemically reactive he pa to toxin by the cytochrome P450 system/ and in vitro studies with hepatocytes have implicated CYP2E1 as the cytochrome P450 isoform responsible for cytotoxic metabolite formation (29). 

Reactivation of latent tuberculosis is a major concern with infliximab (SEDA-26, 402), and accounts for about one-third of infections in these patients. According to data from the manufacturers, 130 cases of active tuberculosis were notified up to October 2001. Many of the cases were disseminated or extrapulmonary tuberculosis, and several patients died. Several case reports have provided detailed information in at least seven other patients, including three who developed miliary tuberculosis and one who developed Mycobacterium tuberculosis enteritis (44-48). A detailed analysis of 70 cases of tuberculosis reported to the FDA has been published (49). Two-thirds of the cases were noted after three or fewer infusions and 57% of the patients had extrapulmonary disease. There were 64 cases from countries with a low incidence of tuberculosis. From these reports and the number of patients treated with infliximab, the estimated rate of tuberculosis in patients with rheumatoid arthritis treated with infliximab was four times higher than the background rate. Patients with evidence of active infection should not receive infliximab until the infection is under control all should be screened for tuberculosis before starting infliximab (50). From these and other data it has been estimated that the risk of tuberculosis in the first year of infliximab treatment is 0.035 in US citizens and 0.2% in non-US citizens. Further investigations, such as a chest X-ray and a Mantoux test, and prophylactic treatment with isoniazid, will show whether the incidence can be reduced in patients taking anti-TNF treatment (51). 

Nunez Martinez O, Ripoll Noiseux C, Carneros Martin JA, Gonzalez Lara V, Gregorio Maranon HG. Reactivation tuberculosis in a patient with anti-TNF-alpha treatment. Am J Gastroenterol 2001 96(5) 1665-6. 

Single dose infusions of iron dextran appear to have increased the occurrence of malaria in endemic regions. There was an increased mortality after oral or parenteral iron therapy in children with severe malnutrition (kwashiorkor), perhaps due to overwhelming infections (36). Reactivation of quiescent infections of various other types has been observed in African nomads following ferrous sulfate therapy (SEDA-4,171). Iron dextran has similarly been associated with a flaring up of latent tuberculosis in children. 

Cautions Thromboembolic disorders, history of tuberculosis (may reactivate disease), hypothyroidism, cirrhosis, nonspecific ulcerative colitis, CHF, hypertension, psychosis, renal insufficiency, seizure disorders. Prolonged therapy should be discontinued slowly. 

Infliximab has been related to adverse effects such as infusion reactions, serum sickness, sepsis, and reactivation of tuberculosis. Infusion reactions and serum sickness relate to the immune response to foreign protein. Patients often develop anti-infliximab antibodies with multiple infusions. Serum sickness has occurred in patients who received infliximab doses separated by a long period of time. Sepsis and tuberculosis may occur because of the inhibition of TNF-protective mechanisms. 

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