The role of anti-TNF inhibitors, such as Infliximab, is increasing for the treatment of inflammatory bowel disease, rheumatoid arthritis, and other disease processes. The risk of infections is increased in patients treated with these agents, in particular, infections associated with T-helper cell impairment such as reactivation of latent tuberculosis and opportunistic fungal infections (eg, histoplasmosis).1-3 Currently, there is no standard measurement of immune function in patients treated with these agents. It is recommended that patients have a tuberculin skin test prior to treatment, but in these patients the test is not reliable given their suppressed immune function.
ImmuKnow (Cylex, Columbia, Md) is a novel in vitro assay for measuring cell function of stimulated T cells.4 It functions on the principle of incubating target T cells with phytohemagglutinin and measuring the production of intracellular ATP as a reflection of cell metabolism. ImmuKnow function assay has been licensed by the Food and Drug Administration for monitoring the immune system of transplant patients.5 Experience and value of this test in other immunosuppressed patients are limited.
We report a case of a patient with inflammatory bowel disease who developed miliary histoplasmosis while on Infliximab. We measured immune function using ImmuKnow assay through treatment of the infection and follow up.
A 53-year-old man, with Crohn disease, developed fever, malaise, and a nonproductive cough 2 weeks prior to presentation. He had been receiving Infliximab injection at 5 mg/kg (500 mg) every 6 to 8 weeks for the past 18 months, with excellent control of his inflammatory bowel disease. A 5TU tuberculin skin test was negative prior to treatment with Infliximab. He was initially diagnosed with bronchitis and was treated with Moxifloxacin as an outpatient. After 1 week of antibiotics with no clinical improvement, patient was admitted to Cleveland Clinic for further evaluation. His last Infliximab injection was 4 weeks prior to presentation at Cleveland Clinic. On examination, he appeared ill with fever, tachycardia, and tachypnea. A chest radiograph showed miliary infiltrate (Fig. 1) and he was hospitalized for pneumonia. Because of the concern for possible tuberculosis, he was placed in respiratory isolation. A bronchoscopy and transbronchial biopsy showed well-formed granulomas but special stains were negative for AFB, fungi, and bacteria.
He was empirically treated with amphotericin B, ceftriaxone, and azithromycin. He improved during the first 3 days of hospitalization and discharged on hospital day 7 on oral itraconazole 200 mg twice a day and oral azithromycin 500 mg once a day. At 1 week of follow up, the fungal serologies showed histoplasmosis yeast antibody by complement fixation titers to be 1:128 with a positive M band on fungal immunodiffusion antibody, as well as a positive histoplasmosis urine antigen test (>2.0). Convalescent fungal serologies at 8 weeks showed a 4-fold rise in histoplasmosis yeast antibody (1:1024) with conversion of the histo mycelial antibody from <1:8 to 1:256 by complement fixation. All cultures for tuberculosis, Legionella, fungi, and respiratory viruses were negative at 6 weeks. He received 6 months of itraconazole treatment. A follow-up chest x-ray showed complete resolution of the miliary infiltrates. He received another Infliximab injection 16 weeks after admission for Crohn disease, after his immune function normalized as measured by ImmuKnow assay immunologic evaluation.
The patient's CD4 counts and immune function were measured using ImmuKnow assay during the acute phase of illness and convalescent period through 52 weeks (see Fig. 2). CD4 counts were measured using flow cytometry. The following number of cluster designated antibodies were used: CD3 and CD4; CD13 and CD45 were used for gating. No other lymphocyte subsets were evaluated.
The data show a significant decrease in immune function, as measured by a decrease in ATP production, whereas the absolute CD4 counts (600) is in the reference range. The T-cell function increased with treatment of infection and discontinuation of Infliximab. Notably, while the CD4 counts decreases with Infliximab injection, CD4 remains within the reference range throughout the course of infection. The immune function is depressed despite a normal CD4 count.
As immunosuppressive medications are being used more widely in a variety of diseases, we need a better assay of our immune system than could be obtained from a routine white blood cell count and CD4 counts. This case illustrates that a patient can have a normal CD4 count and still have poor immune function.
The half life of Infliximab is 9.5 days, however, the immune effect is detectable 4 weeks after the last Infliximab dose. The clinical efficacy of Infliximab, in Crohn disease, is based on local anti-inflammatory and immunomodulatory effects in the bowel mucosa, without generalized suppression of systemic immune functions, as measured by the traditional method of white blood cell counts and lymphocyte subsets, in Crohn disease patients. Our patient's CD4 counts remained normal throughout the course of his illness, while his immune function, as measured by ImmuKnow assay, is depressed during the initial course of the illness and again after another Infliximab injection 16 weeks after admission.
Figure 2 shows a parallel increase and a decrease in CD4 counts and immune function. However, the CD4 counts remain normal throughout the course of illness, yet the immune function did not normalize until 8 weeks after the last Infliximab injection. This is consistent with the fact that Infliximab exerts an immunomodulatory effect without generalized suppression of the lymphocytes.6 The patient's CD4 counts would not have suggested that his immune system is suppressed early in the course of his illness. If patient's immune function has been monitored instead of CD4 counts, this might have been more of a concern for opportunistic infections earlier in the course of his illness.
This report is limited to a single patient who developed an opportunistic infection while on anti-TNF inhibitor. His immune function was depressed at the time of his miliary disease but is still functional. This was observed by (1) well-formed granulomas on lung tissue and "pauci fungal disease," suggesting the immune system was able to contain the histoplasmosis to a certain degree; (2) ImmuKnow testing showed moderate impairment of T-cell function at the time of the diagnosis.
We cannot determine how much of the immune function depression was due to anti-TNF and how much was due to infection, as we had no prior testing of immune function at the onset of treatment with Infliximab. However, prospective studies of patients using immune function assays are needed to determine whether the ImmuKnow assay could be used to help clinicians monitor immune function of a patient on Infliximab. Knowing the immune function could help determine who may be at risk for opportunistic infections or who may require more immunosuppression. ImmuKnow potentially gives clinicians a better picture and flavor of a patient's immune system than can be gleaned from routine blood cell counts, as is the current practice. Further study would be needed to see if anti-TNF could be titrated, by monitoring the immune function, to achieve a good balance of disease control and immune function.
1. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with Infliximab, a tumor necrosis factor α-neutralizing agent. N Engl J Med
2. Wood KL, Hage CA, Knox KS, et al. Histoplasmosis after treatment with anti-tumor necrosis factor-alpha therapy. Am J Respir Crit Care Med
3. Wallis RS, Broder MS, Wong JY, et al. Granulomatous infectious diseases associated with tumor necrosis factor antagonist. Clin Infect Dis
4. Schulick RD, Weir MB, Miller MW, et al. Longitudinal study of in vitro CD4+ T helper cell function in recently transplanted renal allograft patients undergoing tapering of their immunosuppressive drugs. Transplantation
5. Kowalski R, Post D, Schneider MC, et al. Immune cell function testing: an adjunct to therapeutic drug monitoring in transplant patient management. Clin Transplant
6. Cornillie F, Shealy D, D'Haens G, et al. Infliximab induces potent anti-inflammatory and local immunomodulatory activity but no systemic immune suppression in patients with Crohn's disease. Aliment Pharmacol Ther