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A Patient with De Novo Tuberculosis during Anti-Tumor Necrosis Factor—α Therapy Illustrating Diagnostic Pitfalls and Paradoxical Response to Treatment

  1. Sandra M. Arend1,
  2. Eliane M. S. Leyten1,
  3. Willeke P. J. Franken1,
  4. Erik M. Huisman2, and
  5. Jaap T. van Dissel1
  1. 1Department of Infectious Diseases, Leiden University Medical Center, Leiden
  2. 2Municipal Health Service, The Hague, The Netherlands
  1. Reprints or correspondence: Dr. Sandra M. Arend, Dept. of Infectious Diseases, C5P-39, Leiden University Medical Center, P.O.Box 9600, 2300 RC Leiden, The Netherlands (s.m.arend{at}lumc.nl).

  1. Presented in part: Rethinking the Epidemiology of Tuberculosis Infection—The First Global Symposium on Interferon-γ Assays, Vancouver, British Columbia, Canada, 21–22 February 2007 (abstract 016).

 
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Abstract

In 2005, a 24-year-old man with Crohn disease who had been treated with infliximab for several months was exposed to an individual with smear-positive tuberculosis. Soon after exposure, he complained of malaise, dry cough, and weight loss. Despite normal chest radiograph findings and negative tuberculin skin test results, tuberculosis was considered to be the most likely diagnosis. The results of a whole-blood assay for detection of interferon-γ production in response to Mycobacterium tuberculosis—specific antigen were positive. Acid-fast staining and polymerase chain reaction of bronchoalveolar lavage fluid samples had negative results, but M. tuberculosis was cultured. After the initiation of 4 antitubercular drugs and the discontinuation of infliximab therapy, the patient developed an immune reconstitution syndrome accompanied by enlarged mediastinal lymph nodes and multiple intrapulmonary miliary lesions. This case of de novo tuberculosis during anti-tumor necrosis factor α treatment illustrates the uncharacteristic presentation of the disease and the elusiveness of the diagnosis, as well as the fact that discontinuation of anti-tumor necrosis factor α treatment can be accompanied by an immune reconstitution syndrome similar to that observed in human immunodeficiency virus-infected individuals with tuberculosis.

Treatment with antagonists of TNF-α (anti-TNF-α) has had a major impact on the treatment of several disabling inflammatory disorders, such as rheumatoid arthritis and Crohn disease. In 2001, it was first reported that these drugs importantly increase the risk of reactivation tuberculosis (TB) [1, 2]. TB can be difficult to diagnose in patients who are treated with immunosuppressive agents, such as anti-TNF-α, and the response to treatment can be unpredictable [3, 4]. Therefore, screening for the presence of latent M. tuberculosis infection is now routinely performed before starting treatment with anti-TNF-α [5–7]. Nevertheless, TB continues to be reported in patients during anti-TNF-α treatment [8]. In part, this may be related to the limited sensitivity of the tuberculin skin test in patients who are already immunosuppressed as the result of previous treatment [7, 9]. In addition, de novo infection can occur, which obviously cannot be prevented through screening. This case report illustrates various clinical pitfalls and complications that can be encountered in patients with TB during anti-TNF-α treatment.

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Case Report

In July 2005, a 24-year-old man who had received a diagnosis of Crohn disease in 1998 (patient A) was referred to our hospital (Leiden University Medical Center; Leiden, The Netherlands). He was born in The Netherlands of Cape Verdian parents. He had been treated with azathioprine for several years, which was intermittently administered in combination with prednisone in varying dosages. After negative tuberculin skin test (TST) screening results and negative chest radiograph screening findings in August 2004, patient A received 4 doses of the TNF-α blocking agent infliximab (Remicade; Centocor) between August 2004 and May 2005 in combination with 10 mg of prednisone administered daily. On 11 July 2005, patient A visited the Municipal Health Service (The Hague, The Netherlands) as part of a contact investigation, because a Cape Verdian colleague (patient B) had received a diagnosis of smear-positive pulmonary TB (Ziehl-Neelsen +5). Patient A and patient B had carpooled to work for 1 h every working day during the previous 2 weeks. Chest radiograph findings were reported to be normal and unchanged, compared with findings of radiographs obtained before starting anti-TNF-α treatment. TST was not performed, because it was considered to be unreliable as a result of patient A's use of immunosuppressive drugs. Patient A was referred to Leiden University Medical Center for expert consultation.

Patient A reported fatigue, night sweats, and dry cough of several weeks' duration and had noted weight loss of 3 kg but no fever. On physical examination, he appeared to be moderately ill and had a dry cough. Laboratory results showed an elevated erythrocyte sedimentation rate of 114 mm in the first hour, moderate anemia (hemoglobin level, 7.8 mmol/L), and an elevated lactate dehydrogenase level of 569 IU/L (normal level, <450 IU/L). Because anti-TNF-α is known to mask clinical symptoms and signs of infection, TB was strongly suspected despite the negative radiographic findings. TST was performed and resulted in a 0-mm induration; however, the QuantiFeron-TB Gold in-tube assay (Cellestis), an in vitro whole-blood assay for the detection of IFN-γ production in response to Mycobacterium tuberculosis–specific antigens, was positive (IFN-γ level, 3.48 IU/mL). The results of acid-fast staining and PCR of bronchoalveolar lavage fluid samples were negative for M. tuberculosis complex. The clinical course is shown in figure 1. While awaiting culture results, treatment for TB with 4 drugs was started, and infliximab therapy was withheld. After 3 weeks, the BACTEC MGIT 960 (BD Biosciences) culture (fluid medium) became positive for fully susceptible M. tuberculosis with an IS6110 restriction fragment-length polymorphism fingerprint pattern that was identical to that of the isolate obtained from patient B (figure 2), indicating primary progressive or de novo M. tuberculosis infection.

Figure 1
View larger version:
Figure 1

Timeline of the clinical course of a patient with de novo tuberculosis (TB) during anti-TNF-α therapy. The asterisk indicates intermittent episodes of glucocorticosteroid treatment. Boxed numbers indicate clinical features representing the learning points of the case, as follows: (1) screening for latent Mycobacterium tuberculosis infection may be insensitive in patients already using immunosuppressive drugs and is ineffective with regard to future TB exposure; (2) primary infection in patients during anti-TNF-α treatment involves a high risk of immediate progressive and disseminated TB; (3) radiographic findings and TST results may be false-negative in this setting; (4) a novel whole-blood-based, TB-specific in vitro assay had positive results and helped to detect M. tuberculosis infection (these tests can produce false-negative results, however, and cannot differentiate between active TB and latent M. tuberculosis infection); (5) direct results of tests performed on BAL fluid may be negative, but culture can be positive; and (6) treatment of TB in association with discontinuation of anti-TNF-α treatment may lead to severe immune reconstitution disease with clinical and radiographic features. BAL, bronchoalveolar lavage; E, ethambutol; ESR, erythrocyte sedimentation rate; H, isoniazid; LTBI, latent M. tuberculosis infection; MTB, M. tuberculosis; R, rifampin; TST, tuberculin skin test; X-chest, chest radiograph findings; Z, pyrazinamide; ZN, Ziehl-Neelsen staining.

Figure 2
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Figure 2

Restriction fragment-length polymorphism (RFLP) fingerprint pattern of Mycobacterium tuberculosis isolates. IS6110 RFLP genotype of patient A and his colleague (patient B) showing identical patterns.

Several days after starting TB treatment, patient A's fatigue increased, and he now, for the first time, developed a fever up to 39°C. After 2 weeks of treatment, the fever had subsided, but his weight had further decreased to 49 kg (before this episode, his weight had been 56 kg), the dry cough was now continuous, and he noticed chest pain on inspiration. Serum transaminase levels were normal at that time. Chest radiograph findings now revealed mediastinal lymphadenopathy, whereas a CT scan showed multiple intrapulmonary miliary nodules. One month after starting treatment for TB, 3 sputum samples were found to be positive for auramine, with +1 on Ziehl-Neelsen staining, and were found to be culture positive for fully susceptible M. tuberculosis. No other infection was diagnosed, and the clinical deterioration was attributed to an immune reconstitution syndrome. By January 2006, the cough had finally stopped. After a prolonged illness, the clinical course was favorable, but a chest radiograph still showed abnormalities, with persistent hilar lymphadenopathy and intrapulmonary nodules at the end of 12 months of treatment. These had improved but not yet completely resolved 1 year later. Limited activity of Crohn disease allowed gradual discontinuation of all immunosuppressive drugs, and there has been no need for restarting anti-TNF-α treatment to date.

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Discussion

This case report illustrates several remarkable and clinically relevant aspects of TB occurring during treatment with TNF antagonists. It demonstrates the occurrence of de novo TB after initiating therapy with TNF antagonists, the potentially rapid progression to active TB following exposure, negative radiographic findings despite disseminated lung disease, the finding of a false-negative TST result in association with a positive result of a TB-specific whole-blood assay, and a paradoxical response to antitubercular agents.

Limitations of screening before initiation of therapy with TNF antagonists. Reactivation TB during treatment with TNF antagonists is a now well-recognized clinical entity, and the implementation of recommendations regarding the management of latent M. tuberculosis infection has importantly decreased the TB rate among patients who are treated with anti-TNF-α, despite the well-known limitations of the TST [10]. However, even optimal screening and treatment for latent TB before starting anti-TNF-α therapy does not prevent the occurrence of de novo TB following exposure at any later time. In that regard, it has been suggested that annual TSTs be performed [11]. The prevalence of positive TST results in native Dutch individuals in our patient's age category is ∼1%, indicating that the risk of exposure among the general population is low. In certain populations, such as immigrants, homeless persons, drug abusers, prison inmates, or those who have contact with any of these groups, the risk of TB exposure is higher. Our patient was infected by a colleague, and the exposure could have been neither foreseen nor prevented. Genetic fingerprinting of the M. tuberculosis isolate provided conclusive evidence of the recent transmission. Empirical treatment of latent M. tuberculosis infection in patients receiving anti-TNF-α treatment who have been in close contact with an individual with a proven smear-positive case of TB would involve the risk of treating subclinical TB disease with monotherapy and the subsequent development of drug resistance. A thorough clinical evaluation, therefore, is warranted in these circumstances.

Rapid progression to active TB following exposure. Differentiation between primary and reactivation TB should take into account variables, such as the time between anti-TNF-α therapy and the development of TB or recognized exposure to an individual with smear-positive TB, as was clearly what happened in our patient. The clinical course in our patient underscores that TNF antagonists can predispose for early and rapid progression following TB exposure. The absolute risk of TB disease following primary exposure during therapy with TNF antagonists is not known, but it is most likely very high. In persons without immune defects, the lifetime risk of TB is thought to be 10%, with the majority of the cases occurring within 1 year after infection. Available data on the risk of TB disease among immunocompromised patients all refer to the risk of reactivation TB and thus encompass relative risks, compared with subjects without immunosuppression [12, 13]. In patients with HIV infection and a positive TST result, the risk of reactivation TB is as high as 10% per year [14]. Solid-organ transplant recipients have a relative risk of TB reactivation that is 20–74 times higher than that among the general population [15]. Wolfe et al. [13] reported that the risk of TB among patients with rheumatoid arthritis not treated with anti-TNF-α was not different from the rate among the general US population, whereas a study in Korea, which has an intermediate TB burden, demonstrated a higher rate of TB among patients with rheumatoid arthritis than among the general population [16]. In the former study [13], infliximab increased the risk of TB in patients with rheumatoid arthritis from 6.2 cases per 100,000 patients (95% CI, 1.6-34.4 cases per 100,000 patient-years of exposure) to 52.5 cases per 100,000 patient-years of exposure (95% CI, 14.3-134.4 cases per 100,000 patient-years of exposure), and a similar fold increase was found in the Korean study [16]. No cases occurred in persons receiving preventive therapy. However, it must be realized that these figures were derived from unselected patients with rheumatoid arthritis, and the risk of TB reactivation is most likely to be much higher among patients with rheumatoid arthritis receiving infliximab who actually harbor latent M. tuberculosis infection and have not received preventive treatment.

The critical role of TNF in maintaining latent M. tuberculosis infection has been studied in mice [17, 18]. In another study, mice first received anti-TNF-α treatment and were subsequently infected with M. tuberculosis, thus mimicking primary exposure, which is similar to what occurred in our patient. All animals developed almost immediate and rapidly fatal disease [19]. The risk of immediate progression to TB in humans following exposure to M. tuberculosis during use of anti-TNF-α agents is not precisely known, but it can be assumed to be high.

Clinical features of TB during receipt of TNF antagonists. In the initial report by Keane et al. [1] involving 70 cases of TB occurring during receipt of infliximab therapy, extrapulmonary and disseminated TB occurred in 57% and 24% of patients, respectively, which are considerably higher rates than are generally observed in this population. This is pathogenetically understandable in light of the central role of TNF in the development and maintenance of intact granulomas [20]. Apart from the extent of infection, the clinical presentation of TB occurring during treatment with TNF antagonists can be uncharacteristic. In our patient, the chest radiograph did not show abnormalities, whereas the patient had pulmonary symptoms, and M. tuberculosis was isolated from the patient's bronchoalveolar lavage fluid samples. This is similar to findings in HIV-infected subjects; in this population, 10% of patients with pulmonary TB have normal chest radiograph findings, mostly in association with low CD4+ cell counts [21, 22]. The lack of symptoms or objective signs of infection can be explained by the fact that symptoms and signs are often caused by the host immune response and are not directly caused by the infectious agent. Thus, when the clinical suspicion of TB is high, diagnostic procedures should be performed despite the absence of radiographic abnormalities. A case of postmortem diagnosis of TB despite a large number of diagnostic procedures with negative findings has been reported [4]. Early empirical treatment for presumed TB disease without any proof is, however, not the answer, because many other opportunistic or common bacterial infections can occur in patients using TNF antagonists [11, 23–25].

Diagnostic value of the TST and ofM. tuberculosis—specific in vitro assays. The TST is based on delayed-type hypersensitivity to tuberculin and is, therefore, less reliable in patients receiving drugs that affect the cellular immune system or in patients with extensive TB and T cell anergy. The false-negative TST result in our patient, which was obtained after exposure and during immunosuppression with prednisone, azathioprine, and infliximab was, therefore, not surprising. Novel blood tests have become available that detect IFN-γ production in response to specific antigens of M. tuberculosis [26–28]. In our patient, the results of a QuantiFeron TB Gold in-tube whole-blood assay were strongly positive, which strengthened the decision for empirical treatment of TB while awaiting the results of microbiological diagnostic tests. In our patient, the blood test was apparently less affected by immunosuppressive drugs than was the TST. This is in agreement with studies indicating that in vitro IFN-γ release assays perform well in HIV-infected individuals [29–32]. However, a limited sensitivity of QuantiFeron TB Gold for TB has also been reported, and a negative blood test result does not exclude TB [33, 34]. In a clinical population that included many immunocompromised patients, QuantiFeron TB Gold produced indeterminate results because of a failure of response to the positive control antigen more frequently than did T-Spot.TB (Oxford Immunotec), which is another TB-specific blood test that is based on the ELISPOT technique; it uses incubation of a defined number of isolated WBCs and, therefore, is not dependent on the WBC count [35]. A recent study evaluated in-house ELISPOT and other assay formats that are based on TB-specific antigens for screening of patients before the use of anti-TNF-α agents. The finding that some blood tests had better sensitivity and better specificity than the TST for detection of latent M. tuberculosis infection is promising [36]. Further studies are needed to better define the potential role of blood tests for screening before starting anti-TNF-α therapy or the work-up of immunocompromised patients with suspected TB.

Paradoxical response to antituberculosis drugs or immune reconstitution disease. It has been previously suggested that TNF antagonists should ideally be discontinued for the duration of active TB therapy [11, 37]. However, this report shows that an immune reconstitution syndrome can occur that is analogous to that observed during infections in patients coinfected with HIV and M. tuberculosis who are treated with HAART [38]. The syndrome is caused by restoration of the cellular immune system in the presence of an infection, illustrating the important role of the host immune response in the development of symptoms. The occurrence of an immune reconstitution syndrome in patients who developed TB during treatment with TNF antagonists has previously been reported [3, 39]. In all cases, anti-TNF-α treatment had been stopped at the time that TB was diagnosed. Thus, both continuing and stopping anti-TNF-α treatment carry the risk of an adverse clinical course, and at present, it is not clear whether anti-TNF-α treatment can be safely continued or restarted in patients with active TB. In that regard, Matsumoto et al. [40] describe a patient for whom infliximab therapy was discontinued when TB was diagnosed and restarted after 9 months of TB treatment, first in combination with 3 months of isoniazid and rifampin therapy and then in combination with continued use of isoniazid. Matsumoto et al. [40] state that infliximab treatment may be considered for patients who have recovered from TB and for whom anti-TB therapy can be maintained. TNF is a double-edged sword, however, because it is not only essential for the containment of latent M. tuberculosis infection but is also responsible for the weight loss and constitutional symptoms of TB. In that regard, a study involving patients with HIV-associated TB suggested that adjunctive etanercept as immunotherapy is safe during TB treatment and could even be beneficial, whereas corticosteroid therapy was effective but caused severe adverse effects [41, 42]. The benefits and risks of treatment with TNF antagonists during active TB could depend on pharmacodynamic differences between etanercept and neutralizing antibodies, such as infliximab [43].

In HIV-infected patients, the treatment of immune reconstitution symptoms with prednisone can be effective and, provided that mycobacterial resistance and other infections are ruled out as causes of clinical deterioration, this could also be considered in patients treated with TNF antagonists. Although steroids are considered to be useful, the necessary dose and duration of treatment remain unclear. In that regard, it is of note that our patient developed immune reconstitution symptoms during receipt of a 10-mg per day regimen of prednisone. However, the effective dose was probably lower because of enzyme induction resulting from rifampin use and could have been too low to exert a beneficial effect on the immune reconstitution symptoms.

In conclusion, this report illustrates several striking clinical features of TB during treatment with TNF antagonists. Optimal screening for latent M. tuberculosis infection cannot prevent all TB among patients treated with TNF antagonists, primary M. tuberculosis infection may rapidly progress to severe disease, clinical signs of TB can be unreliable or masked during anti-TNF-α therapy, and unremarkable chest radiograph findings do not rule out pulmonary TB. The TST may produce a false-negative result, as was the case in our patient, but a true positive result would have been helpful. A specific blood test for M. tuberculosis had positive results before culture results became available. The occurrence of a severe immune reconstitution syndrome in our patient suggests that the discontinuation of treatment with a TNF antagonist is not without risk. Because many opportunistic infections and common infections have also been described in patients receiving treatment with TNF antagonists, the differential diagnosis and clinical work-up demand an open mind at all stages.

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Acknowledgments

We thank Arnout Mulder of the National Mycobacteria Reference Unit, the Institute of Public Health and the Environment (Bilthoven, The Netherlands), for providing the genetic fingerprint patterns.

Potential conflicts of interest. S.A. has been an invited speaker at a symposium sponsored by Cellestis. All other authors: no conflicts.

  • Received May 7, 2007.
  • Accepted July 13, 2007.
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  1. Clin Infect Dis. (2007) 45 (11): 1470-1475. doi: 10.1086/522993
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