Application and problems of quantiFERON TB-2G for tuberculosis control programs--(2) clinical use of quantiFERON TB-2G

BACKGROUND: QuantiFERON TB-2nd Generation (QFT) is an accurate tool for detecting tuberculosis infection regardless of past history of BCG vaccination. In Japan, QFT test was recognized for diagnostic tool on April 2005, and adopted officially on January 2006. Tuberculosis Society issued Guideline for using QFT-2G on May 2006. PURPOSE: This article describe the usefulness and remarks in clinical use on diagnosis and system for detection of tuberculosis infection among staff in NHO Tokyo Hospital that has 100 beds for tuberculosis. METHOD: (1) QFT test for 403 definite diagnosed tuberculosis patient before tuberculosis treatment or within 7 days chemotherapy in NHO Tokyo Hospital. Seventy-four patients have immunosuppressive diseases such as diabetes mellitus, malignant disease, using corticosteroid or immunosuppressor and HIV+ including overlap diseases. QFT result was analyzed by immunosuppressive diseases and by age for 329 patients who have no immunosuppressive diseases. (2) For control of tuberculosis infection of staff, QFT test is used in 3 situation. One is baseline QFT for staff who are shifted to tuberculosis ward from non-tuberculosis ward and new employee, 2nd is following up for staff who work at tuberculosis ward, and 3rd is contact investigation for staff who work at non-tuberculosis ward. Tuberculin skin testing and baseline QFT were done for 92 staff on April 2006, 2 were shifted to tuberculosis ward from non-tuberculosis ward and 90 were new employee. RESULT: (1) Among 403 definite diagnosed tuberculosis patient before tuberculosis treatment or within 7 days chemotherapy, QFT positive rate was 78.7%. Among 74 patients who have immunosuppressive diseases such as diabetes mellitus, malignant disease, using corticosteroid or immunosuppressor and HIV+ including overlap diseases, QFT positive rate was 58-70%. Among 329 patients who have no immunosuppressive diseases, QFT positive rate was 88-89% in thirties and forties, 69% in sixties and 63% in nineties. QFT-2G test for 134 previously treated tuberculosis cases who are not suffered from active tuberculosis, 49 cases (37%) were positive, 27 cases (20%) were intermediate and 58 cases (43%) were negative. Instructive three cases were reviewed. Suspicion of tuberculosis relapse with QFT negative case was M. avium-intracellulare disease. Suspicion of M. avium-intracellulare disease rather than tuberculosis by X-ray and CT with QFT positive case was tuberculosis. A case with small nodule on CT with QFT positive was adenocarcinoma. (2) Tuberculin Skin Testing and baseline QFT for 92 staff, 4 were QFT positive. Compared with Tuberculin Skin Testing more than 29 mm in erythema, QFT positive rate was 9% and more than 9 mm in induration, QFT positive rate was 7%. By following up QFT test for staff working at tuberculosis ward, 2 staff, one nurse and one helper, were diagnosed tuberculosis infection. As to contact investigation, one nurse was diagnosed tuberculosis infection. CONCLUSION: Although QFT is a very excellent tool for detecting tuberculosis infection, on clinical diagnosis, it is important to mind that QFT depends on clinical condition especially immunosuppressive diseases, aging and past infection. We cannot diagnose or exclude active tuberculosis by QFT result. This is a useful assistant tool on clinical diagnosis.     

Tuberculosis infection transmitted at autopsy

Tuberculosis can be a risk to staff and students in the autopsy room. We report three medical students and one technician who were infected with tuberculosis during two autopsies. In both cases pulmonary tuberculosis had not been diagnosed before death.     

Tuberculosis among health care workers in Okinawa Prefecture]

In health care setting, transmission of M. tuberculosis (TB) is considerable risk not only to patients but to health care workers (HCWs). The total number of registered TB cases in Okinawa prefecture was 1,202 in 1993-1995 (incidence rate 28.3 per 100,000 in 1995) and that of HCWs was 23. Using data from TB registration system, relative risk of tuberculous disease of nurses was estimated to be 2.3 higher than general population. Nosocomial transmission of TB to HCWs in a general hospital was occurred in 1993. After 2 nurses in the same ward were diagnosed as active pulmonary TB by routine screening chest X-ray, a contact investigation was performed in their family, friends and the ward staffs. On the result of initial evaluation of PPD test, 22 of 26 HCWs were suspected to be infected and preventive therapy with isoniazid were given to 16 HCWs. Follow-up chest radiographs for 3 years revealed 5 HCWs were active TB. According to RFLP analysis of M. tuberculosis isolates, 3 HCWs and 1 patient had identical RFLP pattern to 65-year-old female SLE patient, who was admitted for fever in Nov. 1993 and was diagnosed as miliary tuberculosis after 2 weeks admission. As she had no cough and sputum, the infectiousness of the case was suspected to be increased by cough-inducing procedure. The following TB infection control measures were conducted in the hospital; (1) Education and training to all HCWs for early identification of TB patient and adequate treatment (2) Surveillance and reporting system of TB patient from laboratory and ward to infection-control committee (3) Introduction of PPD test program for HCWs (4) Use of HEPA masks as personal respiratory protection. We need further evaluation of engineering controls e.g. ventilation and isolation room.     

Risk factors for nosocomial transmission of multidrug-resistant tuberculosis due to Mycobacterium bovis among HIV-infected patients.

OBJECTIVE: To identify risk factors for transmission of multidrug-resistant tuberculosis (MDR-TB) among hospitalized human immunodeficiency virus (HIV) infected patients exposed during a nosocomial outbreak. DESIGN: Case control study. Cases were HIV-infected patients with MDR-TB due to Mycobacterium bovis (MDR-TBMb) who acquired the disease after exposure to an MDR-TBMb patient in an hospital ward. Controls were HIV-infected patients exposed to a case of MDR-TBMb in an hospital ward but who did not develop MDR-TBMb during the follow-up. RESULTS: Nineteen cases and 31 controls were included. CD4 cell counts were significantly lower among cases. Exposure in the infectious diseases ward or exposure to the index patient were associated with development of MDR-TBMb, while exposure during a single-room hospital stay and exposure in the respiratory isolation ward were associated with non-development of MDR-TBMb. A multiple regression logistic model showed that only a CD4 cell count below 50/microL and exposure to the index patient increased the risk of developing MDR-TBMb (P < 0.05). Hospitalization in a single room seemed to protect HIV-infected patients from developing nosocomial MDR-TBMb (P = 0.052). CONCLUSIONS: Over classic risk factors, such as length of exposure or sharing a room with a case, severe immunosuppression independently increases the risk of MDR-TB transmission in the context of a nosocomial MDR-TB outbreak among HIV-infected patients. This information must be considered in the management of tuberculosis outbreaks. Patients with CD4 cell counts below 50/microL should be the principal group targeted for prevention strategies in nosocomial outbreaks.     

Nosocomial transmission of tuberculosis from unsuspected disease

Tuberculosis remains an occupational hazard for hospital employees. A case of acute generalized tuberculosis occurring in a patient with a malignancy who had received corticosteroids was undetected during life and during a gross autopsy examination. Histologic examination of tissue performed one month later was necessary to establish the diagnosis. Of susceptible hospital staff members who were exposed to the index case, infection developed in nine of 56 (16 percent) compared with three of 333 (0.9 percent) unexposed personnel with similar risk but no known exposure (p less than 0.001). This was a 17.8-fold increase in the infection rate for the exposed group. Three employees infected had evidence of active disease: two had pleural effusions and one had cavitary pulmonary infiltrates; six were asymptomatic. The high rate of infection was associated with inadequate air ventilation and exposure to uncontained infectious aerosol. Preventive therapy with isoniazid, high-change-ventilating systems, ultraviolet radiation, and primary barrier systems are recommended methods to reduce the infection risk.     

Management of an outbreak of Norwegian scabies.

An outbreak of Norwegian scabies in a 170-bed acute care hospital was controlled through an organized plan for delivering treatment to those affected: four patients, 50 staff members, and 14 family members of staff members. Health departments in two counties were notified and found four additional cases in the long-term care facility at which the index patient lived. Contact isolation was used for the index patient and any other patients with nosocomial scabies. Staff members infested with Sarcoptes scabiei were released from work until they had been treated with lindane. Staff members who had been in contact with infested persons and staff members' families were treated prophylactically with lindane. This aggressive treatment plan resulted in rapid resolution of the outbreak.     

Current status of patients discharging Mycobacterium tuberculosis after admission to Kawasaki Medical School Hospital

OBJECTIVES: To investigate the current status of patients with tuberculosis in Kawasaki Medical School Hospital which has closed tuberculosis isolation ward and review the nosocomial tuberculosis infection control. MATERIALS AND METHODS: Clinical analysis was performed and nosocomial tuberculosis infection control were examined in 39 patients from whom Mycobacterium tuberculosis was isolated in Kawasaki Medical School Hospital between January 2001 and August 2004. RESULTS: Mycobacterium tuberculosis was isolated in 16 patients in the Respiratory Division of the Department of Internal Medicine and in 23 patients in non-respiratory divisions. Thirty-four patients had underlying diseases and of these 14 patients had malignant diseases. The final diagnosis was pulmonary tuberculosis in 23 patients, and pulmonary tuberculosis was suspected in 13 patients on admission. The remaining 10 patients were treated for pneumonia on admission. M. tuberculosis was isolated most frequently from the sputum in 21 patients and 13 of them were smear positive who needs nosocomial infection control measures. Health examinations of the families and hospital staff in contact with these 13 patients with smear positive sputum after the diagnosis of tuberculosis revealed no active case of tuberculosis. CONCLUSIONS: This study has shown that there are many cases with an atypical pattern for pulmonary tuberculosis among patients with underlying diseases, especially malignant diseases. There are still many tuberculosis patients who were diagnosed pneumonia after the admission and were administered antibiotics. We believe that more educational guidance regarding tuberculosis is needed for the hospital staff.     

Investigation of a pulmonary tuberculosis outbreak]

Diagnoses of infectious tuberculosis (TB) patients were followed by thorough contact investigation on the basis of our hospital's Infectious Disease Manual ever since an infection of an inpatient with extended hospital stay was confirmed by a positive acid-fast sputum smear in October 1998. In September 2000, a nurse was found to have pulmonary TB and another was given a diagnosis of right tuberculous pleuritis the following November. Contact investigations were expedited among all hospital staff, families of the infected nurses, and all suspected inpatients. Five were diagnosed as TB, 8 were given chemoprophylaxis and 8 others required observation. The result verified a TB outbreak within the hospital, and management of TB infection control was re-enforced subsequently. We concluded that immediate contact investigation promoted successful early diagnosis, and reacknowledged the significance of the health supervision of all staff, operations including the environment and equipment control of the institution, and frequent contact and integration with the administration of the public health center. This experience enabled a useful revision of the disease manual for the future.     

Effectiveness of infection control measures in controlling a nosocomial outbreak of multidrug-resistant tuberculosis among HIV patients in Italy.

SETTING: Between October 1992 and February 1994, 33 cases of multidrug-resistant tuberculosis (MDR-TB) were diagnosed among patients infected by the human immunodeficiency virus (HIV) and hospitalised in an HIV ward in Milan, Italy. This outbreak was part of a much larger outbreak, begun in another hospital and probably transferred through a patient. OBJECTIVE: To evaluate risk factors for transmission and the effectiveness of infection control measures. DESIGN: 1) Active follow-up of exposed patients, 2) cohort study among HIV-infected patients exposed to MDR-TB cases before and after the implementation of control measures, 3) screening of close contacts of MDR-TB cases, and 4) molecular typing by restriction fragment length polymorphism (RFLP) analysis. RESULTS: The risk of MDR-TB was higher in patients with lower CD4+ lymphocyte percentages and longer duration of exposure. No difference in the daily risk was observed for in-patients vs day-hospital patients or by room distance from an infectious case. Of the 90 patients exposed before the implementation of infection control measures (i.e., October 1992-June 1993) 26 (28.9%) developed MDR-TB, whereas none of the 44 patients exclusively exposed after implementation developed MDR-TB, despite the continuing presence of infectious MDR-TB cases in the ward. CONCLUSION: Simple control measures were effective in significantly reducing nosocomial transmission among patients.     

Outbreak of tuberculosis among middle aged employees in an office

We experienced an outbreak of tuberculosis in a salesmen's office during the period from 1993 to 1997. The outbreak was detected retrospectively. In July, 1997, a 47-year-old man was diagnosed as pulmonary tuberculosis. As he worked with a 42-year-old man who was already registered in our health center, we suspected an outbreak and started a survey. Contact examinations were carried out for 9 employees of his office and 3 members of his friends. As the result of these examinations, one employee showed strongly positive tuberculin skin test, and was indicated isoniazid chemoprophylaxis. Furthermore, some contacts told us that seven cases of active tuberculosis and three cases of primary infection indicated chemoprophylaxis had occurred among employees and their family members. The index case was a 41-year-old man who was diagnosed as tuberculosis in January, 1993. The second case among employees had previous history of pulmonary tuberculosis. Almost the patients among the employees had a hard life suffering from debts, and had heavy alcohol use. These facts may partly explain the spread of tuberculosis in this office. As each case was registered at different health centers, we hadn't noticed the outbreak for 4 years. But it is true that insufficient approach of health centers to contacts caused a serious delay of detecting the outbreak. A thorough investigation for contacts and complete contact examinations are needed.     

Detection of unsuspected cases of nosocomial transmission of tuberculosis by use of a molecular typing method.

The aim of this study was to use restriction fragment length polymorphism to detect unsuspected cases of nosocomial transmission of tuberculosis (TB) among patients who had been admitted to a university hospital. One hundred fifty-one samples of Mycobacterium tuberculosis isolated from patients with pulmonary TB were studied. The isolates from 37 patients (24.5%) defined 11 clusters. None of the patients infected with these cluster isolates had hospital stays that coincided with one another, and for 5.4% of the patients, the epidemiological link was clearly outside the hospital. Previous incarceration was associated with infection with cluster isolates. In addition, 109 patients without TB (41 of whom were infected with human immunodeficiency virus) who shared a room with patients who had TB were followed for 18-60 months. Among the patients who survived, secondary cases of TB due to nosocomial transmission were not detected.     

Risk assessment towards tuberculosis among hospital personnel: administrative control, risk exposure, use of protective barriers and microbial air quality

A recent increase in the rate of tuberculosis among hospital personnel has led to a greater concern about the risk of Mycobacterium tuberculosis transmission in the hospital. A cross-sectional study was conducted to assess the risk of tuberculosis infection among hospital personnel of a governmental hospital in Bangkok by applying hospital tuberculosis control strategies, including administrative control, risk exposure, use of protective barriers when in contact with TB patients, and microbial air quality in the studied wards. Fourteen members of the infection control committee (ICC) and 118 hospital personnel were interviewed regarding the infection control policy and its implementation. The history of TB exposure at work and the use of protective barriers when in contact with TB patients were recorded for the studied hospital personnel. Air samples in the studied wards were collected to investigate bacterial and fungal counts. The results reveal that all the studied ICC members and more than 85% of studied hospital personnel knew the infection control policy and attempted to implement it. However, 35.71, 37.50, 80.90,93.93, and 88.46% of personnel working in ER, OPD, ICU, female medical ward, and male medical ward, respectively, implemented the TB isolation policy. More than 80% of studied personnel had histories of exposure to TB patients, but only 52.73% (31.57% in OPD to 80.00% in ICU) used the appropriate barriers (N95) when in contact with TB patients. Air samples collected from the studied wards, except ICU, had high bacterial and fungal counts (> 500 cfu/m3). These findings show that hospital personnel working in the studied wards, except ICU, were at risk for tuberculosis infection. The hospital ICC should advertise the use of TB standard precautions to hospital personnel and provide a ventilation system for reducing the microbial counts in the air of the studied wards.     

Environmental factors relating to a mass outbreak of tuberculosis in a junior high school

OBJECTIVE: To clarify environmental factors relating to a mass outbreak of tuberculosis. METHODS: A 15-year old girl, a third-grade student of a junior high school (the index case) was found to have smear-positive cavitary pulmonary tuberculosis. Among 718 subjects who underwent contacts investigation, the rates of infection and cases among different exposure groups were compared. The ventilation rate within the room of the junior high school was analyzed using sulfur hexafluoride (SF6) as the tracer gas. RESULTS: Up to 56 months after the detection of the index case, a total of 34 tuberculosis patients were newly diagnosed, and 155 persons were subjected to chemoprophylaxis. The rates of infection were 90.0% among homeroom classmates and 60.8% among other classmates, respectively. Out of the subjects who had only indirect contact with the index case, 11 patients were diagnosed. Most of the windows of the building were of the fixed sash type, permitting only low ventilation ranging from about 1.6 to 1.8 room air change per hour. When sliding doors of the room were opened, the SF6 concentration in the room was rapidly mixed up with that in the passage. CONCLUSION: Low ventilation of the room and overcrowding contributed to the high infection rate among homeroom classmates. Infectious droplet nuclei spread to the passage at recess. The homeroom of the index case was located in front of the building's entrance. The index case used some common rooms of the building. In addition to these environmental factors, other factors, especially the high infectiousness of the index case also contributed to the mass outbreak.     

Multi-drug resistant tuberculosis (MDRTB)

MDRTB has been made by treatment failure and has also spread by its contagiousness. I tried to explain how to make MDRTB clinically, and also tried to propose how to prevent it from spreading in a hospital. At first, a principle of modem chemotherapy against tuberculosis was elucidated, i.e. "bi-phase method of treatment." Danger of mono-therapy, particularly functional one, was warned through a case report. Thus acquired drug-resistance was made, single at first, multi-drug thereafter. According to the increase of patients of acquired MDRTB, primary MDRTB patient has emerged through the direct contagion. We reported nosocomial outbreak cases of MDRTB, including re-infection to patients with pan-sensitive tuberculosis. Therefore, strict isolation of MDRTB with smear-positive sputum must be instituted in a tuberculosis ward. All smear-positive tuberculosis patients should be isolated in a room against air-borne infection just in case of MDRTB. There are, however, not enough isolation rooms in tuberculosis ward in Japan. Rapid detection of rifampicin-resistance through the gene analysis must be done in this situation.     

Infection control in a teaching hospital without a tuberculosis ward]

Approximately 30 cases of tuberculosis are diagnosed in our hospital each year. Because three of our nurses contracted tuberculosis in 1998, we implemented the following control measures for tuberculosis : (1) immediate examination, diagnosis, and treatment in suspected cases; (2) screening of all health-care workers with a two-step tuberculin skin test (TST); (3) examination of all persons exposed to tuberculosis-infected persons; and (4) greater awareness of tuberculosis. We offered prophylactic medications to all exposed persons with a TST reaction greater than 20 mm. These control measures increased the numbers of outpatients who were examined and treated, and decreased the prevalence of tuberculosis among long-term inpatients. High-risk indices also decreased over a 2-year period. Forty-seven staff members showed TST reactions, and 5 of them received prophylactic medication. No cases of tuberculosis developed in staff members exposed to tuberculosis-infected persons. However, tuberculosis developed in one staff member who had a strong TST reaction at the start of employment. In this case, results of TSTs previously administered to all health-care workers was useful for estimating the prevalence of infection. We used a new method for diagnosing tuberculosis in 27 persons believed to be infected. Of these 27 persons, 5 (19%) showed reactions greater than pseudopositive reactions and were given prophylactic medication. Early diagnosis of infected persons, examination of persons exposed to tuberculosis, and greater disease awareness are important measures for monitoring tuberculosis and controlling its spread.     

Norovirus outbreaks in a teaching hospital: the role of infection control

In January 2004, 20 patients and 19 staff in one ward became ill in an outbreak of norovirus-related gastroenteritis over a 12-day period. The epidemic curve indicated person-to-person transmission. Infection control measures were instituted in consultation with the government health authorities. A prompt rigorous response may have prevented spread to other wards. In March 2004, 54 staff and 1 member of a patient's family became ill in an outbreak of gastroenteritis. The source of norovirus contamination was associated with food served at the hospital restaurant. Secondary infection was prevented because the outbreak was recognized early and staff members with gastroenteritis symptoms were asked to stay home. Immediate control measures, such as identification and announcement of the outbreak, isolation of symptomatic individuals from others, personal protection, helped control the infection.     

Tuberculosis outbreak among inpatients]

The Index case, 22 year-old pregnant woman, was admitted for threatened abortion among obstetric ward in X Hospital for 17 days. Two months later, she was admitted for delivery among perinatal ward in another Y Hospital for 5 days. She produced persistent cough and sputum, when she had diagnosed pulmonary tuberculosis (TB) with sputum smear-positive and cavity on 2nd Y hospital day. By 2 years after the detection, 15 TB patients were newly diagnosed. Seven of 15 TB patients were culture positive cases and RFLP analysis of the 7 Mycobacterium TB strains demonstrated an identical banding pattern, thus confirming the spread of a unique strain. Of the 15 TB patients, seven were patients on the obstetric ward. Three were visitors. Two were infants with TB meningitis and miliary TB were not confirmed direct contact with the index case. Another two were family member and one was employee. The present outbreak emphasizes the high risk of TB transmission on obstetric and perinatal ward when the diagnosis of smear-positive pulmonary TB was delayed.     

Molecular epidemiological investigation of an outbreak of Pseudomonas aeruginosa infection in an SCT unit

From May to October 2006, six severe Pseudomonas aeruginosa infections were diagnosed in patients undergoing SCT in the SCT unit of the Careggi hospital (Florence, Italy). Four of the infected patients were treated consecutively in the same room (room N). On the hypothesis of a possible environmental source of infection, samples were collected from different sites that had potential for cross-contamination throughout the SCT unit, including the electrolytic chloroxidant disinfectant used for hand washing (Irgasan) and the disinfectant used for facilities cleaning. Four of the environmental samples were positive for P. aeruginosa: three Irgansan soap samples and a tap swab sample from the staff cleaning and dressing room. The AFLP (amplified fragment length polymorphism) typing method employed to evaluate strain clonality showed that the isolates from the patients who had shared the same room and an isolate from Irgasan soap had a significant molecular similarity (dice index higher than 0.93). After adequate control measures, no subsequent environmental sample proved positive for P. aeruginosa. These data strongly support the hypothesis of the clonal origin of the infective strains and suggest an environmental source of infection. The AFLP method was fast enough to allow a 'real-time' monitoring of the outbreak, permitting additional preventive measures.     

Missed TB in AIDS unit leads to tighter isolation

The San Francisco General Hospital recently tightened its tuberculosis (TB) policies for isolating HIV-positive patients after learning that active TB patients had been admitted without respiratory protection. The new policy resulted from what was initially believed to be a TB outbreak on the AIDS unit. However, an investigation concluded that the patients were infected outside the hospital. The hospital now automatically screens patients for TB when they are admitted to the AIDS ward. HIV-positive patients who are put on rule-out for TB cannot be admitted to the AIDS unit until they have three negative sputum smears. Low-risk, suspected TB patients now are put in a private room with negative air pressure. This new policy will cost the hospital more money. Using the rapid assay test for sputum-positive cases that are likely to be Mycobacterium avium complex (MAC) would cut isolation time and money. However, the test is only 95 percent sensitive, so one out of 20 patients could be missed. The city will be making a decision about whether the new test will be used under these circumstances.     

The outbreak and control of Ebola viral haemorrhagic fever in a Ugandan medical school

Uganda has just experienced the largest outbreak of Ebola haemorrhagic fever (EHF) ever recorded. Mbarara University Teaching Hospital (MUTH) is responsible for training approximately one-third of Uganda's doctors. Mbarara is located in SouthWest Uganda, 614 km from Gulu, the main epicentre of the outbreak. On 23 October a patient was admitted to the medical ward of MUTH with an acute fever. He soon exhibited haemorrhagic symptoms and died. He was later confirmed to have suffered Ebola. Three more patients subsequently contracted the disease. All died. There were no further cases in Mbarara. No members of staff or medical student was infected. We give details of the clinical features of those patients who contracted the disease, the setting up of an Ebola isolation unit, the case surveillance and the search for the source of the outbreak. The implications for similar institutions in East Africa are discussed.