Kashef Ijaz

Integrating genome-based informatics to modernize global disease monitoring, information sharing, and response.

The rapid advancement of genome technologies holds great promise for improving the quality and speed of clinical and public health laboratory investigations and for decreasing their cost. The latest generation of genome DNA sequencers can provide highly detailed and robust information on disease-causing microbes, and in the near future these technologies will be suitable for routine use in national, regional, and global public health laboratories. With additional improvements in instrumentation, these next- or third-generation sequencers are likely to replace conventional culture-based and molecular typing methods to provide point-of-care clinical diagnosis and other essential information for quicker and better treatment of patients. Provided there is free-sharing of information by all clinical and public health laboratories, these genomic tools could spawn a global system of linked databases of pathogen genomes that would ensure more efficient detection, prevention, and control of endemic, emerging, and other infectious disease outbreaks worldwide.

National Survey to Measure Rates of Liver Injury, Hospitalization, and Death Associated with Rifampin and Pyrazinamide for Latent Tuberculosis Infection

BACKGROUND Cases of severe and fatal liver injury were reported after a 2-month course of rifampin-pyrazinamide therapy was recommended in 2000 as an alternative to isoniazid for treatment of latent tuberculosis infection. We estimated rates of rifampin-pyrazinamide-associated liver injury and compared these with historical rates for isoniazid. METHODS We conducted a survey of state and city tuberculosis programs and other health care settings in the United States where rifampin-pyrazinamide was prescribed. The number of rifampin-pyrazinamide therapy initiations was collected, as well as the number of occurrences of (1) asymptomatic aspartate aminotransferase serum concentration >5 times the upper limit of normal, (2) symptomatic hepatitis (in which the patient was not hospitalized), (3) hospitalization for liver injury, (4) death with liver injury, and (5) treatment completion. We also searched a national pharmacy claims database (Verispan). Rates of these events were calculated. RESULTS Among 139 programs, 110 (79%) responded; 87 (79%) had initiated rifampin-pyrazinamide therapy for a total of 8087 patients between January 2000 and June 2002. Rates per 1000 rifampin-pyrazinamide therapy initiations during this period were 25.6 (95% confidence interval [CI], 22.3-29.3) for asymptomatic aspartate aminotransferase level >5 times the upper limit of normal and 18.7 (95% CI, 15.9-21.9) for hepatitis. Seven fatalities and 23 hospitalizations occurred, with rates of 0.9 (95% CI, 0.4-1.9) and 2.8 (95% CI, 1.8-4.3) per 1000 rifampin-pyrazinamide therapy initiations, respectively. Of 8087 patients, 64% completed rifampin-pyrazinamide therapy. The Verispan search revealed 1 rifampin-pyrazinamide-associated hospitalization (2.9 hospitalizations per 1000 rifampin-pyrazinamide therapy initiations; 95% CI, 0.1-18.4) and no deaths. Articles on the use of isoniazid therapy for latent tuberculosis infection that were published after 1990 reported fatality rates of 0.0-0.3 deaths per 1000 persons. CONCLUSIONS Rates of liver injury, hospitalization, and death associated with rifampin-pyrazinamide therapy exceed rates reported for isoniazid therapy. Because earlier randomized trials of rifampin-pyrazinamide lacked adequate statistical power to detect fatal events, the Centers for Disease Control and Prevention recommends that rifampin-pyrazinamide generally should not be used for treatment of latent tuberculosis infection.

Unsuspected Recent Transmission of Tuberculosis among High-Risk Groups: Implications of Universal Tuberculosis Genotyping in Its Detection

BACKGROUND The initiation of universal genotyping revealed 3 clusters of 19 patients with tuberculosis (TB) in Wisconsin, with no apparent epidemiologic links among most of them. An epidemiologic investigation was conducted to determine whether genotype clustering resulted from recent transmission. METHODS We conducted additional interviews with patients and reviewed medical records. Places frequented by the patients while they were infectious were visited to identify contacts. RESULTS Our investigation revealed several previously unrecognized possible sites of TB transmission: a single-room occupancy hotel, 2 homeless shelters, 1 bar, and 2 crack houses. Seven patients with previously diagnosed TB were added to the clusters. Of 26 patients, we identified epidemiologic links for all but 1. Common risk factors among patients included alcohol abuse, crack cocaine use, homelessness, and unemployment. Additionally, 98 contacts missed during routine contact investigation were identified. CONCLUSIONS Transmission of TB, particularly among high-risk groups, may go undetected for years. Our investigation demonstrated the value of universal genotyping in revealing unsuspected recent TB transmission and previously unrecognized sites of transmission, which can be targeted for specific TB interventions.

Multidrug-Resistant Tuberculosis Outbreak among US-bound Hmong Refugees, Thailand, 2005

Enhanced pre-immigration screening and program expansion decreased TB importation.

Severe or Fatal Liver Injury in 50 Patients in the United States Taking Rifampin and Pyrazinamide for Latent Tuberculosis Infection

BACKGROUND Severe liver injuries were attributed to the rifampin and pyrazinamide (RZ) regimen after it was recommended for treating latent tuberculosis infection. Implicating RZ as the likeliest cause required excluding alternative causes. METHODS US health departments reported data on patients who died or were hospitalized for liver disease within 1 month after taking RZ for latent tuberculosis infection from October 1998 through March 2004. The circumstances were investigated on site for each case. Illness characteristics, reasons for RZ treatment, doses and frequency of administration of pyrazinamide, monitoring during treatment, and causes of liver injury were determined. RESULTS Liver injury was attributable to RZ use for all 50 patients reported, 12 of whom died. For 47 patients, RZ was the likeliest cause of liver injury. The median patient age was 44 years (range, 17-73 years). Thirty-two patients (64%) were male. Seven (16%) of 43 patients tested had hepatitis C virus antibodies, 1 (2%) of 45 had chronic hepatitis B, 3 (14%) of 22 had positive results of HIV serologic tests, 34 (71%) of 48 had alcohol use noted, and 33 (66%) of 50 were taking additional hepatotoxic medications. Six patients, 2 of whom died, had no predictors for liver disease. Patients who died were older (median age, 52 vs. 42 years; P=.08) and took a greater number of other medications (median number of medications, 4 vs. 2; P=.05) than did those who recovered, but these 2 factors were correlated (P<.01). Thirty-one patients (62%) were monitored according to guidelines, 9 of whom died. CONCLUSIONS RZ was the likeliest cause of most of these liver injuries, some of which were fatal in spite of monitoring. Fatality was predicted by age or use of other medications, but none of the cofactors showed promise as a reliable clinical predictor of severe liver injury.

Transmission network analysis to complement routine tuberculosis contact investigations.

OBJECTIVE We examined the feasibility and value of network analysis to complement routine tuberculosis (TB) contact investigation procedures during an outbreak. METHODS We reviewed hospital, health department, and jail records and interviewed TB patients. Mycobacterium tuberculosis isolates were genotyped. We evaluated contacts of TB patients for latent TB infection (LTBI) and TB, and analyzed routine contact investigation data, including tuberculin skin test (TST) results. Outcomes included number of contacts identified, number of contacts evaluated, and their TST status. We used network analysis visualizations and metrics (reach, degree, betweenness) to characterize the outbreak. RESULTS secondary TB patients and more than 1200 contacts. Genotyping detected a 21-band pattern of a strain W variant. No HIV-infected patients were diagnosed. Contacts prioritized by network analysis were more likely to have LTBI than nonprioritized contacts (odds ratio=7.8; 95% confidence interval=1.6, 36.6). Network visualizations and metrics highlighted patients central to sustaining the outbreak and helped prioritize contacts for evaluation. CONCLUSIONS A network-informed approach to TB contact investigations provided a novel means to examine large quantities of data and helped focus TB control.

Tuberculosis Outbreak Investigations in the United States, 2002–2008

To understand circumstances of tuberculosis transmission that strain public health resources, we systematically reviewed Centers for Disease Control and Prevention (CDC) staff reports of US outbreaks in which CDC participated during 2002–2008 that involved >3 culture-confirmed tuberculosis cases linked by genotype and epidemiology. Twenty-seven outbreaks, representing 398 patients, were reviewed. Twenty-four of the 27 outbreaks involved primarily US-born patients; substance abuse was another predominant feature of outbreaks. Prolonged infectiousness because of provider- and patient-related factors was common. In 17 outbreaks, a drug house was a notable contributing factor. The most frequently documented intervention to control the outbreak was prioritizing contacts according to risk for infection and disease progression to ensure that the highest risk contacts were completely evaluated. US-born persons with reported substance abuse most strongly characterized the tuberculosis outbreaks in this review. Substance abuse remains one of the greatest challenges to controlling tuberculosis transmission in the United States.

Unrecognized Tuberculosis in a Nursing Home Causing Death with Spread of Tuberculosis to the Community

OBJECTIVES: To determine the reason for an increase in tuberculin skin test (TST) conversion in employees in a nursing home and to determine the source case responsible for spread of tuberculosis (TB) in two nursing homes and a hospital in a rural part of Arkansas using molecular and traditional epidemiological methods.

What We Are Watching—five top global infectious disease threats, 2012: a perspective from CDC’s Global Disease Detection Operations Center

Disease outbreaks of international public health importance continue to occur regularly; detecting and tracking significant new public health threats in countries that cannot or might not report such events to the global health community is a challenge. The Centers for Disease Control and Prevention’s (CDC) Global Disease Detection (GDD) Operations Center, established in early 2007, monitors infectious and non-infectious public health events to identify new or unexplained global public health threats and better position CDC to respond, if public health assistance is requested or required. At any one time, the GDD Operations Center actively monitors approximately 30–40 such public health threats; here we provide our perspective on five of the top global infectious disease threats that we were watching in 2012: (1) avian influenza A (H5N1), (2) cholera, (3) wild poliovirus, (4) enterovirus-71, and (5) extensively drug-resistant tuberculosis.

Mycobacterium tuberculosis transmission between cluster members with similar fingerprint patterns.

Molecular epidemiologic studies provide evidence of transmission of Mycobacterium tuberculosis within clusters of patients whose isolates share identical IS6110-DNA fingerprint patterns. However, M. tuberculosis transmission among patients whose isolates have similar but not identical DNA fingerprint patterns (i.e., differing by a single band) has not been well documented. We used DNA fingerprinting, combined with conventional epidemiology, to show unsuspected patterns of tuberculosis transmission associated with three public bars in the same city. Among clustered TB cases, DNA fingerprinting analysis of isolates with similar and identical fingerprints helped us discover epidemiologic links missed during routine tuberculosis contact investigations.