Xpert MTB/RIF Assay Shows Faster Clearance of Mycobacterium tuberculosis DNA with Higher Levels of Rifapentine Exposure.

The Xpert MTB/RIF assay is both sensitive and specific as a diagnostic test. Xpert also reports quantitative output in cycle threshold (CT) values, which may provide a dynamic measure of sputum bacillary burden when used longitudinally. We evaluated the relationship between Xpert CT trajectory and drug exposure during tuberculosis (TB) treatment to assess the potential utility of Xpert CT for treatment monitoring. We obtained serial sputum samples from patients with smear-positive pulmonary TB who were consecutively enrolled at 10 international clinical trial sites participating in study 29X, a CDC-sponsored Tuberculosis Trials Consortium study evaluating the tolerability, safety, and antimicrobial activity of rifapentine at daily doses of up to 20 mg/kg of body weight. Xpert was performed at weeks 0, 2, 4, 6, 8, and 12. Longitudinal CT data were modeled using a nonlinear mixed effects model in relation to rifapentine exposure (area under the concentration-time curve [AUC]). The rate of change of CT was higher in subjects receiving rifapentine than in subjects receiving standard-dose rifampin. Moreover, rifapentine exposure, but not assigned dose, was significantly associated with rate of change in CT (P = 0.02). The estimated increase in CT slope for every additional 100 µg · h/ml of rifapentine drug exposure (as measured by AUC) was 0.11 CT/week (95% confidence interval [CI], 0.05 to 0.17). Increasing rifapentine exposure is associated with a higher rate of change of Xpert CT, indicating faster clearance of Mycobacterium tuberculosis DNA. These data suggest that the quantitative outputs of the Xpert MTB/RIF assay may be useful as a dynamic measure of TB treatment response.

Medium matters: modeling the impact of solid medium performance on tuberculosis trial sample size requirements.

SETTING: Two-month solid medium culture conversion is a commonly used, if suboptimal, endpoint for phase 2 anti-tuberculosis treatment trials. OBJECTIVE AND DESIGN: To model the effect of the performance characteristics (sensitivity and contamination rate) of solid medium on required sample size for a two-arm clinical trial with 85% true (gold standard) culture conversion in the control and 95% in the experimental arm. RESULTS: Increasing sensitivity and decreasing contamination reduced the sample size from 239 subjects/arm (60% sensitivity, 30% contamination) to 138 subjects/arm (95% sensitivity, 1% contamination). CONCLUSION: Optimizing solid medium has significant potential to reduce sample size and increase the efficiency of tuberculosis clinical trials.

Three months of weekly rifapentine plus isoniazid is less hepatotoxic than nine months of daily isoniazid for LTBI.

SETTING: Nine months of daily isoniazid (9H) and 3 months of once-weekly rifapentine plus isoniazid (3HP) are recommended treatments for latent tuberculous infection (LTBI). The risk profile for 3HP and the contribution of hepatitis C virus (HCV) infection to hepatotoxicity are unclear. OBJECTIVES: To evaluate the hepatotoxicity risk associated with 3HP compared to 9H, and factors associated with hepatotoxicity. DESIGN: Hepatotoxicity was defined as aspartate aminotransferase (AST) >3 times the upper limit of normal (ULN) with symptoms (nausea, vomiting, jaundice, or fatigue), or AST >5 x ULN. We analyzed risk factors among adults who took at least 1 dose of their assigned treatment. A nested case-control study assessed the role of HCV. RESULTS: Of 6862 participants, 77 (1.1%) developed hepatotoxicity; 52 (0.8%) were symptomatic; 1.8% (61/3317) were on 9H and 0.4% (15/3545) were on 3HP (P < 0.0001). Risk factors for hepatotoxicity were age, female sex, white race, non-Hispanic ethnicity, decreased body mass index, elevated baseline AST, and 9H. In the case-control study, HCV infection was associated with hepatotoxicity when controlling for other factors. CONCLUSION: The risk of hepatotoxicity during LTBI treatment with 3HP was lower than the risk with 9H. HCV and elevated baseline AST were risk factors for hepatotoxicity. For persons with these risk factors, 3HP may be preferred.

A large-scale, rapid public health response to rabies in an organ recipient and the previously undiagnosed organ donor.

This article describes and contrasts the public health response to two human rabies cases: one organ recipient diagnosed within days of symptom onset and the transplant donor who was diagnosed 18 months post-symptom onset. In response to an organ-transplant-related rabies case diagnosed in 2013, organ donor and recipient investigations were conducted by multiple public health agencies. Persons with potential exposure to infectious patient materials were assessed for rabies virus exposure. An exposure investigation was conducted to determine the source of the organ donor's infection. Over 100 persons from more than 20 agencies spent over 2700 h conducting contact investigations in healthcare, military and community settings. The 564 persons assessed include 417 healthcare workers [5.8% recommended for post-exposure prophylaxis (PEP)], 96 community contacts (15.6% recommended for PEP), 30 autopsy personnel (50% recommended for PEP), and 21 other persons (4.8% recommended for PEP). Donor contacts represented 188 assessed with 20.2% recommended for PEP, compared with 5.6% of 306 recipient contacts recommended for PEP. Human rabies cases result in substantial use of public health and medical resources, especially when diagnosis is delayed. Although rare, clinicians should consider rabies in cases of encephalitis of unexplained aetiology, particularly for cases that may result in organ donation.

Frequency, severity and duration of immune reconstitution events in HIV-related tuberculosis.

SETTING: Patients were enrolled in a prospective trial of rifabutin-based tuberculosis (TB) treatment for human immunodeficiency virus related TB. Antiretroviral therapy (ART) was encouraged, but not required. OBJECTIVE: To evaluate the frequency, risk factors and duration of immune reconstitution events. DESIGN: Patients were prospectively evaluated for immune reconstitution events, and all adverse event reports were reviewed to identify possible unrecognized events. RESULTS: Of 169 patients, 25 (15%) developed immune reconstitution events related to TB. All 25 were among the 137 patients who received ART during TB treatment, so the frequency in this subgroup was 18% (25/137). Risk factors for an immune reconstitution event in multivariate analysis were Black race, the presence of extra-pulmonary TB and a shorter interval from initiation of TB treatment to initiation of ART. The most common clinical manifestations were fever (64%), new or worsening adenopathy (52%) and worsening pulmonary infiltrates (40%). Twelve patients (48%) were hospitalized for a median of 7 days, six underwent surgery and 11 had needle aspiration. The median duration of events was 60 days (range 11-442). CONCLUSION: Immune reconstitution events were common among patients receiving ART during TB treatment, produced substantial morbidity and had a median duration of 2 months.

Syphilitic hepatitis in HIV-infected patients: a report of 7 cases and review of the literature.

BACKGROUND: A recent resurgence of primary and secondary syphilis has been observed in certain population groups, particularly among persons infected with human immunodeficiency virus (HIV). Liver involvement is an infrequently recognized complication of early syphilis, with no previous reports among HIV-infected patients. METHODS: We describe 7 cases of syphilitic hepatitis in HIV-positive individuals and review the literature. RESULTS: At our institutions, all patients presented with a rash consistent with secondary syphilis. Each case was characterized by a conspicuous increase in serum alkaline phosphatase level (mean level +/- standard deviation, 905 +/- 523.6 IU/L) and milder elevations in serum transaminase levels. The mean CD4+ absolute T cell count was 317 cells/mm3, and the median rapid plasma reagin (RPR) titer was 1 : 128. There was a significant correlation between higher CD4+ cell counts and the RPR titers (R=0.93; P=.002). Symptomatic resolution and biochemical improvement, particularly a significant decrease in serum alkaline phosphatase levels (P=.02), occurred following antibiotic therapy. CONCLUSIONS: Hepatic dysfunction is not uncommon in HIV-infected persons and is attributable to multiple causes. In the appropriate clinical setting, syphilitic hepatitis is an easily diagnosed and reversible etiology of liver dysfunction. The recognition of this entity will prevent unnecessary evaluation of abnormal liver enzyme levels in HIV-positive patients.

Kikuchi disease presenting as a flu-like illness with rash and lymphadenopathy.

Kikuchi-Fujimoto disease (Kikuchi Disease) is a self-limited and benign systemic lymphadenitis of unknown cause, originally described by Kikuchi and Fujimoto and coworkers in 1972. Although relatively uncommon, it is increasingly discussed in the medical literature. Clinical presentation typically includes adenopathy, particularly cervical, with fever and flu-like symptoms. This constellation of symptoms, in the presence of a characteristic histiocytic necrotizing lymphadenitis, provides the clinicopathologic diagnosis. The immunopathogenesis of Kikuchi disease may lie in a hyperactive response to viral infection. We describe an African American man with Kikuchi disease, unusual in the extent of his rash and debilitation, and in the relapse of his clinical symptoms.

Successful treatment of human immunodeficiency virus-related Castleman's disease with interferon-alpha.

Multicentric Castleman's disease is an atypical lymphoproliferative disorder for which multiple chemotherapeutic regimens have been used without much success. Role of biological response modifiers like interferon used as a single agent is discussed in this case report.

Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid. Tuberculosis Trials Consortium.

BACKGROUND: Rifapentine is a cyclopentyl-substituted rifamycin whose serum half-life is five times that of rifampin. The US Public Health Service Study 22 compared a once-weekly regimen of isoniazid and rifapentine with twice weekly isoniazid and rifampin in the continuation phase (the last 4 months) of treatment for pulmonary tuberculosis in HIV-seropositive and HIV-seronegative patients. This report concerns only the HIV-seropositive part of the trial, which has ended. The HIV-seronegative part will stop follow-up in 2001. METHODS: Adults with culture-positive, drug-susceptible pulmonary tuberculosis who completed 2 months of four-drug (isoniazid, rifampin, pyrazinamide, ethambutol) treatment (induction phase) were randomly assigned 900 mg isoniazid and 600 mg rifapentine once weekly, or 900 mg isoniazid and 600 mg rifampin twice weekly. All therapy was directly observed. Statistical analysis used univariate, Kaplan-Meier, and logistic and proportional hazards regression methods. FINDINGS: 71 HIV-seropositive patients were enrolled: 61 completed therapy and were assessed for relapse. Five of 30 patients in the once-weekly isoniazid/rifapentine group relapsed, compared with three of 31 patients in the twice-weekly isoniazid/rifampin group (log rank chi2=0.69, p=0.41). However, four of five relapses in the once-weekly isoniazid/rifapentine group had monoresistance to rifamycin, compared with none of three in the rifampin group (p=0.05). Patients who relapsed with rifamycin monoresistance were younger (median age 29 vs 41 years), had lower baseline CD4 cell counts (median 16 vs 144 microL), and were more likely to have extrapulmonary involvement (75% vs 18%, p=0.03) and concomitant therapy with antifungal agents (75% vs 9%, p=0.006). No rifamycin monoresistant relapse has occurred among 1004 HIV-seronegative patients enrolled to date. INTERPRETATION: Relapse with rifamycin monoresistant tuberculosis occurred among HIV-seropositive tuberculosis patients treated with a once-weekly isoniazid/rifapentine continuation-phase regimen. Until more effective regimens have been identified and assessed in clinical trials, HIV-seropositive people with tuberculosis should not be treated with a once-weekly isoniazid/rifapentine regimen.

Mycobacterium szulgai infection of the lung: case report and review of an unusual pathogen.

The nontuberculous mycobacteria are responsible for considerable morbidity in the immunocompromised and immunocompetent host, especially in the older patient with chronic fibrotic or cavitary disease of the lung. Mycobacterium szulgai is a slow growing mycobacterium infrequent in nature and man. Except from a snail and a tropical fish, it has been isolated only from humans and nearly always represents a true pathogen. Three-drug therapy using in vitro susceptibilities as a guide for 12 to 18 months increases the likelihood of success. We present a patient who developed M szulgai pulmonary infection 30 years after an episode of pulmonary tuberculosis. After successful therapy for his M szulgai infection, this patient developed chronic pulmonary histoplasmosis. We review the 25 years of clinical experience with this mycobacteria; particular emphasis is on the presentation and treatment of this very unusual infection.

Nontuberculous mycobacterial infections.

The acquired immunodeficiency syndrome (AIDS) pandemic has led to greater understanding and respect for the pathogenic potential of non-tuberculous mycobacteria. Mycobacterium avium complex (MAC) has emerged as the most common systemic bacterial infection in AIDS, causing debilitating disseminated disease in late-stage HIV-infected patients. With the release of the macrolide antibiotics, clarithromycin and azithromycin, effective and well-tolerated therapeutic regimens for MAC have been developed which prolong survival and increase quality of life. The macrolides and rifabutin are also effective as preventive therapy for MAC in patients with AIDS. Mycobacterium kansasii, which causes pulmonary disease similar to tuberculosis as well as disseminated disease in AIDS, is treatable with isoniazid, rifampin and ethambutol. Clinical syndromes and therapeutic options for other non-tuberculous mycobacteria in AIDS are also reviewed.

Nontuberculous mycobacteria in patients with human immunodeficiency virus infection.

Because of their often profound immune suppression, persons with HIV-infection are, increasingly, being identified as having morbidity related to mycobacteria. Indeed, mycobacterial disease is now the second most frequent cause of illness in AIDS patients receiving PCP prophylaxis with the majority of these patients in the United States having disease caused by M. avium complex (MAC). This section reviews the epidemiology, clinical presentation, treatment protocols, and prophylaxis strategies for MAC, as well as the other species of nontuberculosis mycobacteria being diagnosed in the setting of HIV infection. These organisms typically cause extrapulmonary, often disseminated disease in HIV infected persons, although pulmonary disease may occur. The prompt diagnosis and successful treatment of these infections can prolong the life and enhance its quality for affected patients with HIV coinfections.

The impact of human immunodeficiency virus infection on drug-resistant tuberculosis.

Infection with human immunodeficiency virus (HIV) has been associated with increased rates of single- and multidrug-resistant (MDR) tuberculosis in the New York City area. In order to examine the relationship of HIV infection to drug-resistant tuberculosis in other selected regions of the United States, we established a registry of cases of culture-proven tuberculosis. Data were collected from sites participating in an NIH-funded, community-based HIV clinical trials group. All cases of tuberculosis, regardless of HIV status, which occurred between January 1992 and June 1994 were recorded. Overall, 1,373 cases of tuberculosis were evaluated, including 425 from the New York City area, and 948 from seven other metropolitan areas. The overall prevalence of resistance to one or more drugs was 20.4%, and 5.6% of isolates were resistant to both isoniazid and rifampin (MDR). In the New York City area, HIV-infected patients were significantly more likely than persons not known to be HIV-infected, to have resistance to at least one drug (37% versus 19%) and MDR (19% versus 6%). In other geographic areas, overall drug resistance was 16%, and only 2.2% of isolates were MDR. In multiple logistic regression analyses, HIV infection was shown to be a risk factor for drug-resistant tuberculosis, independent of geographic location, history of prior therapy, age, and race. We concluded that HIV infection is associated with increased rates of resistance to antituberculosis drugs in both the New York City area and other geographic areas. MDR tuberculosis is occurring predominantly in the New York City area and is highly correlated with HIV infection.

Cholecystectomy in patients with AIDS: clinicopathologic correlations in 107 cases.

The etiologic and clinical features of cholecystisis in infection due to human immunodeficiency virus (HIV) were studies retrospectively. The charts and histopathologic specimens of 136 HIV-infected patients who underwent cholecystectomy between February 1987 and May 1993 at a large tertiary care center were reviewed. Opportunistic pathogens infecting the 107 patients with AIDS included microsporidia (eight cases-- Enterocytozoon bieneusi in six and Septata intestinalis in two); cytomegalovirus alone (six cases); Cryptosporidium alone (eight cases); cytomegalovirus plus Cryptosporidum (15 cases); and Pneumocystis carinii and Isospora belli (one case each). In addition, histopathologic changes characteristic of Kaposi's sarcoma were seen in one case. Thirty-eight patients with AIDS had acalculous cholecystitis for which no etiologic agent was found. Twenty-eight AIDS patients had cholelithiasis, six with coexistent opportunistic gallbladder infection. In the 107 AIDS patients, no specific symptom was found to be predictive of opportunistic infection of the gallbladder, but such infection was significantly associated with an abnormal abdominal ultrasound (P = .017) and with nonvisualization of the gallbladder by radionucleotide biliary scan (P < .001).

Disseminated toxoplasmosis and acquired immunodeficiency syndrome: diagnosis by transmission electron microscopy.

A 43-year-old, bisexual, black man with acquired immunodeficiency syndrome (AIDS), detected by CD4 lymphocyte criteria alone, presented with low-grade fever, chills, malaise, and watery diarrhea of 2 days' duration. Over the next 5 days, he developed a fulminant septicemia-like illness with progressive hypotension, disseminated intravascular coagulation, and very high serum lactic acid dehydrogenase (2,150 U/L) and serum creatine phosphokinase (5,395 U/L) levels, and died. The cause of this illness was not clinically apparent. A bone marrow biopsy performed on the day of his death revealed intracytoplasmic clusters of 3 microns long, oval, basophilic organisms, the exact nature of which was not evident by light microscopy. The diagnosis of disseminated toxoplasmosis (DT) was made only after electron microscopic study of the bone marrow revealed organisms with features typical of Toxoplasma gondii tachyzoites. These features included a multilayered pellicle, a pointed anterior end containing a conoid, up to nine rhoptries, sparse micronemes, and a posterior end containing a nucleus. Some of the organisms had divided by internal budding or endodyogeny. This case illustrates the value of transmission electron microscopy in making the diagnosis of DT.

Intestinal spirochetosis and acquired immunodeficiency syndrome: ultrastructural studies of two cases.

Two cases of intestinal spirochetosis (IS) with acquired immunodeficiency syndrome are reported. In case 1, a 48-year-old homosexual black man presented with a 1-month history of alternating watery diarrhea and constipation, which dissipated following the removal of two colonic hyperplastic polyps containing IS. In case 2, a 26-year-old homosexual black man presented with a 3-month history of persistent bloody diarrhea and was found to have chronic shigellosis and IS. Pathologic findings of IS were similar in both cases. Basophilic fringes typical of IS covered the surfacing colonic epithelium and consisted of dense growths of spirochetes adherent to and oriented perpendicular to the plasma membranes of the surfacing epithelium. The spirochetes measured 3 to 5 microns in length and 0.2 micron in width, contained four to eight axial fibrils, and closely resembled Brachyspira aalborgi ultrastructurally. These cases are notable because the histopathologic changes of IS were more extensive than generally described. There was involvement of both the right colon and rectum by IS in case 2, and in both cases there was extension of the IS down into the crypts of Lieberkühn, spirochetal invasion of the colonic mucosa, and a conspicuous inflammatory response by macrophages in the underlying lamina propria.