An “indeterminate” QuantiFeron Gold in-Tube (QFT-IT) simply means the result can’t be interpreted. It does NOT mean “intermediate” or “borderline positive”!
Although there are several reasons for an indeterminate QFT-IT, a common explanation is an immunocompromised state involving inadequate T-cell response (eg, corticosteroids, HIV, cancer). Improper storage of tubes and specimen handling, baseline elevated interferon (IFN)-ɣ due to heterophile antibodies, recovery phase of an infection or vaccination may also be associated with indeterminate QFT-IT results. 1,2 For these reasons, the test should be repeated for confirmation.
It all makes more sense if we understand the basis for the test. QFT-IT involves blood obtained in 3 separate test tubes:
- Tube 1: Contains only the patient’s blood with nothing added (NIL) (“Negative control”)
- Tube 2: Contains non-specific mitogens that stimulate patient’s T-cells (“Positive control”)
- Tube 3: Contains specific TB antigens
Since QFT-IT is an IFN- ɣ release assay, IFN- ɣ is measured in each tube after 16-24 h incubation. A negative QFT-IT is when there is not much difference between IFN- ɣ levels in negative control and TB tubes (“TB-[minus]NIL”) AND the positive control works (“MITOGEN-[minus]NIL” is elevated).
You can now see why a negative result in the TB tube doesn’t mean much (ie, the result is “indeterminate”) when the T-cells don’t respond to non-specific antigens. This situation is analogous to calling a PPD “negative” when a patient is anergic!
- Herrera V, Yeh E, Murphy K, et al. Immediate incubation reduces indeterminate results for QuantiFERON-TB Gold in-Tube assay. J Clin Microbiol 2010;48:2672-2676. http://jcm.asm.org/content/48/8/2672.full
- Bui DHP, Cruz AT, Graviss EA. Indeterminate QuantiFERON-TB Gold in-Tube assay results in children. Ped Infect Dis J 2014; 33: 220-22. https://www.ncbi.nlm.nih.gov/pubmed/24413410
Night sweats (NS) is a common patient complaint, affecting about a third of hospitalized patients on medical wards1. Despite its long list of potential causes, direct relationship between the often- cited conditions and NS is usually unclear2, its cause may remain elusive In about a third to half of cases in the primary care setting, and its prognosis, at least in those >65 y of age, does not appear to be unfavorable 2,3.
Selected commonly and less frequently cited conditions associated with NS are listed (Table)2-9. Although tuberculosis is one of the first conditions we think of when faced with a patient with NS, it should be emphasized that NS is not common in this disease (unless advanced) and is rare among hospitalized patients as a cause of their NS1,9.
In one of the larger study of adult patients seen in primary care setting, 23% reported pure NS and an additional 18% reported night and day sweats5; the prevalence of NS in both men and women was highest in 41-55 y age group. In multivariate analyses, factors associated with pure NS in women were hot flashes and panic attacks; in men, sleep disorders.
Table. Selected causes of night sweats
||Less frequently cited
|Neoplastic/hematologic (eg, lymphoma, leukemia, myelofibrosis)
Infections (eg, HIV, tuberculosis, endocarditis)
Endocrine (eg, ovarian failure, hyperthyroidism, orchiectomy, carcinoid tumor, diabetes mellitus [nocturnal hypoglycemia], pheochromocytoma)
Rheumatologic (eg, giant cell arteritis)
|Gastroesophageal reflux disease
Drugs (eg, anti-depressants, SSRIs, donepezil [Aricept], tacatuzumab)
Sleep disturbances (eg, obstructive sleep apnea)
Panic attacks/anxiety disorder
- Lea MJ, Aber RC, Descriptive epidemiology of night sweats upon admission to a university hospital. South Med J 1985;78:1065-67.
- Mold JW, Holtzclaw BJ, McCarthy L. Night sweats: A systematic review of the literature. J Am Board Fam Med 2012; 25-878-893.
- Mold JW, Lawler F. The prognostic implications of night sweats in two cohorts of older patients. J Am Board Fam Med 2010;23:97-103.
- Mold JW, Holtzclaw BJ. Selective serotonin reuptake inhibitors and night sweats in a primary care population. Drugs-Real World Outcomes 2015;2:29-33.
- Mold JW, Mathew MK, Belgore S, et al. Prevalence of night sweats in primary care patients: An OKPRN and TAFP-Net collaborative study. J Fam Pract 2002; 31:452-56.
- Feher A, Muhsin SA, Maw AM. Night sweats as a prominent symptom of a patient presenting with pulmonary embolism. Case reports in Pulmonology 2015. http://dx.doi.org/10.1155/2015/841272
- Rehman HU. Vitamin B12 deficiency causing night sweats. Scottish Med J 2014;59:e8-11.
- Murday HK, Rusli FD, Blandy C, et al. Night sweats: it may be hemochromatosis. Climacteric 2016;19:406-8.
- Fred HL. Night sweats. Hosp Pract 1993 (Aug 15):88.
Patients with newly-diagnosed TB are ~20 times more likely to be coinfected with HIV than those without TB. Unfortunately, the diagnosis of TB in HIV-infected patients is often delayed in part related to its atypical presentation1.
In HIV-infected patients with high CD4 counts, clinical manifestations of TB are usually similar to those without HIV infection (eg, subacute fever, weight loss, cough) with CXR often showing upper lobe infiltrates and/or cavitations typically seen in reactivation TB.
Lower CD4 counts, however, are associated with atypical CXR findings, including pleural effusions, lower or middle lobe infiltrates, mediastinal adenopathy, and lack of cavitary lesions1,2. A normal CXR has been reported in 21% of patients with CD4 <200 cells/μl (vs 5% in those with higher counts)2.
Advanced immune suppression in HIV infection is also associated with negative sputum smears for acid-fast bacilli, concurrent extra-pulmonary disease, and immune reconstitution symptoms after initiation of anti-TB therapy1.
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- Kwan CK, Ernst JD. HIV and tuberculosis: a deadly human syndemic. Clin Microbiol Rev 2011;24:351-376. https://cmr.asm.org/content/24/2/351
- Greenberg, SD, Frager D, Suster B, et al. Active pulmonary tuberculosis in patients with AIDS: spectrum of radiographic findings (including a normal appearance). Radiology 1994;193:115-9. https://pubs.rsna.org/doi/abs/10.1148/radiology.193.1.7916467
ADA is an enzyme found in a variety tissues and blood cells including erythrocytes and lymphocytes. Its activity in body fluids is primarily related to the number, maturation and level of stimulation of lymphocytes (1). Although ADA has been used as a diagnostic test for tuberculous meningitis, pericarditis and pleural effusions, caution should be exercised when interpreting its activity in ascitic fluid, particularly in low endemic countries where cirrhosis may not be uncommon. In a study of patients with ascites in the U.S., the overall sensitivity of the ADA for TB peritonitis was 59 % with a specificity of 95% (1). Among cirrhotic patients, however, the sensitivity of ADA was only 30%! False-positive results are occasionally observed in bacterial peritonitis and malignancy-associated ascites (1). Parenthetically, the sensitivity of serum ascites-albumin gradient (SAAG) <1.1 for TB peritonitis is also low (50%) in the setting of chronic liver disease (2).
- Hillebrand DJ, Runyon BA, Yasmineh WG, Rynders GP. Ascitic fluid adenosine deaminase insensitivity in detecting tuberculous peritonitis in the United States. Hepatology 1996;24:1408-1412.
- Shakil AO, Korula J, Kanel GC, Murray NG, Reynolds TB. Diagnostic features of tuberculous peritonitis in the absence and presence of chronic liver disease: a case-control study. Am J Med 1996;100:179-185.
Although cachexia , a loss of >5% body weight over 12 months, has been reported in about 30% of patients with cancer, many other chronic conditions commonly encountered in our hospitalized patients may also be a culprit. In fact, cachexia is not infrequent in CHF (20%), COPD (20%), kidney failure (40%), or rheumatoid arthritis (10%) (1,2). We also shouldn’t overlook HIV and tuberculosis as a cause.
Cachexia is a multifactorial disease which does not fully reverse with nutritional support. Numerous mediators have been implicated, including cytokines such as tumor-necrosis factor-α, and interleukin [IL]-1 and -6, as well as transforming growth factors such as myostatin and activin A (2).
In patients with CHF, angiotensin II appears to be a key mediator, associated with insulin resistance, depletion of ATP in skeletal muscles, poor appetite, reduction in insulin-like growth factor-1 (IGF-1), and an increase in glucocorticoid and IL-6 levels. All these factors contribute to “cardiac cachexia” through muscle wasting, reduced food intake and lower muscle regeneration.
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- Morely JE, Thomas DR, Wilson M-M G. Cachexia: pathophysiology and clinical relevance. Am J Clin Nutr 2006;83:735-43. https://www.ncbi.nlm.nih.gov/pubmed/16600922
- Yoshida T, Delafontaine P. Mechanisms of cachexia in chronic disease states. Am J Med Sci 2015;35:250-256. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587350/
There is relative dearth of data addressing this very important issue. A decreased IG response after mitogen stimulation during treatment with oral prednisolone has been reported (1).
In a study of patients with autoimmune disorders, 27% of patients on daily prednisolone dose of 10 mg or more had indeterminate QuantiFeron Gold In-Tube test compared to 1% of patients not taking prednisolone (1).
A meta-analysis of the performance of IGRAs (including T-SPOT.TB) concluded that these assays were negatively affected by immunosuppressive therapy (2). So, until more data becomes available, caution is advised in interpreting lack of positive test or indeterminate results of IGRAs in patients on corticosteroid therapy.
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1. Belard E, Semb S, Ruhwald M, et al. Prednisolone treatment affects the performance of the QuantiFERON Gold In-Tube test and the Tuberculin skin test in patients with autoimmune disorders screened for latent tuberculosis infection. Inflamm Bowel Dis 2011;17:2340-2349. https://academic.oup.com/ibdjournal/article/17/11/2340/4631016
2. Shahidi N, Fu Y-T, Qian H, et al. Performance of interferon-gamma release assays in patients with inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis 2012;18:2034-2042. https://www.researchgate.net/publication/265093409_Performance_of_Interferon-gamma_Release_Assay_for_Tuberculosis_Screening_in_Inflammatory_Bowel_Disease_Patients