Rare Case of Concomitant Pulmonary Tuberculosis and Cytomegalovirus Infection in an Immunocompetent Patient

To the Editor: The concurrence of active pulmonary tuberculosis (TB) and influenza in immunocompetent hosts is rarely reported. Such concurrence could distract clinicians from diagnosing TB during an influenza epidemic. We describe 7 cases of concurrent active pulmonary TB and influenza A(H1N1)pdm09 virus infection in South Korea. At 2 teaching hospitals in Seoul, medical records were reviewed retrospectively. Among the 12,196 patients for whom A(H1N1)pdm09 infection was confirmed by real-time reverse transcription PCR from May 2009 through May 2011, a total of 7 (0.06%) were co-infected with newly diagnosed active pulmonary TB (Table). Patients who had a history of TB diagnosis were excluded. Table Case summary of concurrent active pulmonary TB and influenza A(H1N1)pdm09 infection* Among the 7 co-infected patients, 6 (85.7%) were <30 years of age. All but 1 patient, who had colon cancer, had been previously healthy. No patients had diabetes mellitus or HIV infection. One patient was a current smoker. For 5 patients, pulmonary TB was diagnosed within 1 week from the date of influenza diagnosis; initial chest radiographic findings were suggestive of active TB or pneumonia. Another 2 patients, for whom radiographic examination was not performed at the first visit, experienced worsening cough and blood-tinged sputum after improvement of influenza; laboratory tests for TB were performed, and pulmonary TB was diagnosed 17 days after the date of influenza diagnosis. For 4 patients, computed tomography of the chest was performed, and multiple nodular lesions, cavities, and tree-in-bud appearance were found. Lymphopenia at initial visit was detected in 2 patients. All Mycobacterium tuberculosis isolates were sensitive to anti-TB drugs, and clinical outcomes were good for all patients. For persons infected with M. tuberculosis, lifetime risk for development of active TB is 5%–10%; this risk increases for those with immunocompromising conditions (1). One study reported that pulmonary TB was a risk factor for A(H1N1)pdm09 infection (2). However, the concurrence of influenza and pulmonary TB has been reported only a few times, and the findings have been mostly descriptive and somewhat contradictory. An old report, from 1919, describes TB diagnoses for patients who were not recovered completely from influenza pneumonia (3). During 1957–1958, Lofgren and Callans (4) observed 46 patients with newly detected TB that had been diagnosed shortly after Asian influenza; among them, 4 had a history of typical influenza. In South Africa, among 72 patients who died of A(H1N1)pdm09 infection, 7 also had active TB (5). In Taiwan, TB and A(H1N1)pdm09 infection in a lung cancer patient was reported (6). In Japan, a fatal case of influenza pneumonia combined with Streptococcus pneumoniae and M. tuberculosis infection in a patient with diabetes mellitus was reported (7). Although the 2 patients from Taiwan and Japan had concurrent illnesses, 6 of the 7 patients in our study had been healthy (6,7). Radiographic abnormalities for the patients reported here were similar to those reported for other patients, but more cavitary lesions were found for the patients reported here. Although it is not clear whether influenza accelerates emergence of TB, some animal studies suggest that influenza-associated TB is possible. In mouse studies, simultaneous injection of tubercle bacilli into the peritoneum and intranasal inoculation with influenza A virus (PR8) resulted in more rapid and extensive development of pulmonary tuberculous lesions than did infection with tubercle bacilli only (8). In a mouse model of chronic infection with M. bovis BCG, acute infection with influenza virus moderately increased the load of acid-fast bacilli in the liver, although this change was not significant (9). It is possible that temporary suppression of T-cell immunity by A(H1N1)pdm09 virus might alter the course of M. tuberculosis infection. Among influenza patients, CD4+ T cells were depleted and a subset of Th17 cells were preferentially lost at an early stage of infection; Th17 cells that produce proinflammatory cytokine interleukin-17 are associated with a protective immune response (10). Among 4 patients for whom laboratory examination was conducted at initial visit, 2 were lymphopenic. However, individual lymphocyte subsets were not checked, and a functional assay of lymphocytes was not conducted. Further studies of serial quantification and functional assay of lymphocytes at the acute stage of influenza and its effect on host susceptibility to TB in animals and humans are needed. The concurrence of TB and influenza could be a simple overlap. In 2009, the case notification rate of pulmonary TB in South Korea was 58.2 cases per 100,000 population; in 2010, it was 56.5. However, if influenza actually amplifies TB, TB might be underestimated and missed in influenza patients. Thus, large-scale observational epidemiologic studies on the changing incidence of TB during the influenza postpandemic era are needed. Especially in TB-endemic areas, physicians should consider a concurrent pulmonary TB diagnosis for influenza patients with radiologic abnormalities consistent with TB or with prolonged respiratory symptoms.

Introduction The HIV/AIDS pandemic has led to a rise in the incidence of tuberculosis and an epidemic of co-infection in many developing countries. Treatment of Mycobacterium tuberculosis in persons with HIV infection presents several challenges to the clinician, particularly in resource-poor countries. As will be discussed in this paper, diagnosis of latent tuberculosis relies on tuberculin skin testing, which has poor sensitivity and reproducibility in immunocompromised patients. The World Health Organization (WHO) recommends treatment of active tuberculosis as the primary means of global tuberculosis control. In practice, treatment of active tuberculosis typically requires that a symptomatic patient self-report to a health service for evaluation and management. Even if this approach to tuberculosis control were sufficient, many logistic and clinical problems remain involving tuberculosis diagnosis and therapy in the patient with HIV/AIDS. Recognizing the significant clinical and public health challenges surrounding the treatment of tuberculosis in patients with HIV infection, this paper will address a number of issues relevant to the care of co-infected patients. These include current guidelines for the treatment of active tuberculosis, as well as the diagnosis and treatment of latent tuberculosis in HIV-positive patients. The paper concludes with a discussion of promising new drugs for tuberculosis treatment. Epidemiology of tuberculosis and HIV co-infection It is estimated that one-third of the world population is infected with M. tuberculosis, the large majority of whom live in the developing world. The HIV pandemic of the past two decades has led to a rise in the incidence of tuberculosis, particularly in sub-Saharan Africa. There is now an emerging pandemic of patients with HIV infection who are co-infected with tuberculosis. As of December 2000, the WHO estimated that approximately 36.1 million persons worldwide are living with HIV and nearly one-third of these persons are co-infected with M. tuberculosis[1]. Approximately 68% of persons co-infected with HIV and tuberculosis live in sub-Saharan Africa, while 22% live in Southeast Asia. In the United States, the Centers for Disease Control and Prevention (CDC) estimates that approximately 40% of new tuberculosis cases among persons aged 15-44 years occur among individuals with HIV infection or AIDS. Tuberculosis rates among HIV-infected individuals in the United States, however, vary significantly among different groups, with highest rates among intravenous drug users and those who are foreign-born. Today, the burden of tuberculosis and HIV infections largely impacts the developing world, as well as the minority and low socio-economic individuals within industrialized countries. This paper will discuss issues in the treatment of M. tuberculosis in patients with HIV/AIDS; however, it is important to recognize that many patients co-infected with HIV and M. tuberculosis have limited or no access to essential diagnostic and therapeutic strategies. Escalating tuberculosis case rates over the past decade are largely attributable to HIV. Immunity to M. tuberculosis is partly under the control of the MHC class II restricted CD4 cells. With the progressive loss of CD4 cells, patients with HIV infection are at increased risk of reactivation of latent tuberculosis, as well as primary tuberculosis infection [2]. In turn, active tuberculosis infection appears to upregulate HIV replication, resulting in further immune compromise and accelerated HIV disease progression [3,4]. As a result, patients with HIV infection and active tuberculosis are at increased risk of opportunistic infections and associated mortality. The case fatality rate by the end of tuberculosis treatment is approximately 20% for new sputum smear-positive cases and up to 50% for new smear-negative cases [5]. Tuberculosis is the leading cause of death among persons with HIV/AIDS worldwide [6]. Guidelines for the treatment of active tuberculosis This section will review recent guidelines for the treatment of tuberculosis published by the Tuberculosis Committee of the Infectious Disease Society of America (IDSA) in conjunction with the American Thoracic Society (ATS) and the CDC [7,8]. In addition, we will review the Directly Observed Treatment Short-course (DOTS) strategy of the WHO for tuberculosis control worldwide. These published guidelines pertain to the treatment of tuberculosis without respect to the patient's HIV status. Modified recommendations for the treatment of tuberculosis in HIV-seropositive patients will be discussed in the following section. In April 2000, the IDSA published practice guidelines for the treatment of tuberculosis [7]. Table 1, adapted from the IDSA publication, lists the 10 essential recommendations for the treatment of patients with tuberculosis. Readers are referred to the original publication for detailed comments pertaining to these recommendations, as well as performance indicators. It should be noted that the IDSA recommendations were developed for use in industrialized nations such as the United States and are currently not feasible in many countries of the world. In Table 1, therefore, we have juxtaposed the WHO DOTS strategy guidelines for management of patients with tuberculosis.Table 1: Infectious Disease Society of America (IDSA) recommendations and World Health Organization Directly Observed Treatment Shortcourse (WHO DOTS) strategy for the management of patients with tuberculosis (TB).In geographic areas where ≥ 4% of the M. tuberculosis isolates are resistant to isoniazid, the IDSA, ATS, and CDC recommend that the usual three-drug regimen of isoniazid, rifampin and pyrazinamide be augmented with a fourth drug, either ethambutol or streptomycin. Clinicians will therefore need to be aware of the susceptibility patterns in their geographic area. In 1997, approximately 84% of the US population lived in states that had ≥ 4% of tuberculosis isolates resistant to isoniazid. Therefore, most patients in the United States should be started on an initial four-drug regimen. This is followed by isoniazid and rifampin for 18 weeks. Although a 6-month course of treatment is recommended, this should be extended to 9 months if there is a delay in AFB, culture conversion or clinical improvement for 8 weeks. The WHO Global Tuberculosis Programme (WHO/GTP) assists over 60 countries with national tuberculosis control and prevention. The priority of the WHO program has been active case finding and cure of infectious tuberculosis cases. In 1993, the WHO/GTP declared tuberculosis a global emergency and began promoting the DOTS strategy. The DOTS strategy consists of five key components: "1) Government commitment to sustained TB control activities; 2) Case detection by sputum smear microscopy among symptomatic patients self-reporting to health services; 3) Standardized treatment regimen of six to eight months for at least all confirmed sputum smear positive cases, with directly observed treatment (DOT) for at least the initial two months; 4) A regular, uninterrupted supply of all essential anti-tuberculosis drugs; and 5) A standardized recording and reporting system that allows assessment of treatment results for each patient and of the TB control programme performance overall" [9] (see Table 1). According to the WHO/GTP, as of 1999, 127 countries had accepted the DOTS strategy and were implementing it to varying degrees [10]. Nevertheless, the WHO/GTP estimate that, in 1999, only 45% of the world population had access to DOTS and 23% of new smear-positive cases were referred to DOTS programs. In addition, there are often a complex array of political, financial, and infrastructure problems that impede local DOTS programs. The current WHO DOTS strategy does not incorporate the diagnosis and treatment of latent tuberculosis. Some experts believe that the DOTS strategy, which focuses exclusively on the treatment of active cases, is insufficient for the control and elimination of tuberculosis, particularly in the HIV/AIDS era [11]. It has been recommended that targeted diagnosis and treatment of latent tuberculosis infection among specific populations be added to national tuberculosis control programs. At present, WHO recommends treatment of latent tuberculosis in HIV-positive patients; but only in settings where it is possible to provide HIV testing and counseling, and where it is possible to exclude cases of active tuberculosis and ensure proper follow-up. The DOTS strategy also employs empiric anti-tuberculous therapy without mycobacterial cultures and drug susceptibility testing. Without drug susceptibility information, it is impossible to identify cases of drug-resistant tuberculosis and to avoid treatment failure and further transmission of drug-resistant strains. The WHO recognizes the threat of multidrug-resistant tuberculosis (MDR-TB) and, in July 1999, convened a working group on DOTS-Plus for the treatment of MDR-TB [12]. DOTS-Plus is a pilot program to provide second-line drugs (i.e., fluoroquinolones, amikacin, kanamycin, capreomycin, cycloserine, para-aminosalicylic acid, and ethionamide) to manage MDR-TB in resource-limited countries. This strategy does not, however, address the role of mycobacterial cultures and drug susceptibility testing for individualized drug therapy and the prevention of drug-resistant tuberculosis. Finally, because DOTS relies on patients self-reporting to health services, additional tuberculosis transmission can take place before the patient is evaluated and receives appropriate therapy. Modeling of the tuberculosis epidemic in Tanzania suggests that DOTS may slow the incidence rate, but in the face of the HIV epidemic is unlikely to reverse the upward trend [13]. Again, some experts advocate targeted case finding, particularly among high-risk groups [11,14]. Diagnosis and treatment of active tuberculosis infection in patients with HIV infection This section deals specifically with the treatment of active tuberculosis in HIV-infected individuals as recommended by the CDC [15,16]. Again, many people co-infected with HIV and tuberculosis in the developing world do not have access to the relevant diagnostic tests and anti-tuberculosis and antiretroviral therapies. To impact tuberculosis-associated morbidity and mortality worldwide, developing countries will require both the skills and commodities to diagnose and treat individuals effectively. At present, tuberculosis treatment for the HIV-positive patient as recommended by the CDC is not applicable in most resource-poor countries. Treatment of active and latent tuberculosis infection in patients with HIV depends on the application of both clinical judgment and appropriate diagnostic tests. Active tuberculosis can occur at any CD4 cell count but atypical presentations are more likely with advanced HIV disease or AIDS. Clinicians should be alert to the sometimes atypical presentations of pulmonary and extrapulmonary tuberculosis in HIV-infected patients. Sputum acid fast staining, mycobacterial cultures, and drug susceptibility testing are recommended in all patients suspected of having tuberculosis. However, patients with HIV are slightly less likely to have positive sputum smears than non-HIV-infected individuals [17]. Likewise, chest radiographic findings can vary depending on the degree of immunosuppression. Patients with CD4 cell counts greater than 200 are more likely to have classic findings of upper lobe infiltrates with cavitary lesions, while those patients with AIDS may more likely have hilar adenopathy and pleural effusions without cavitations [18]. Mycobacteremia and extrapulmonary tuberculosis, especially meningitis and adenopathy, also correlate with diminishing numbers of CD4 cells and degree of immunosuppression. Thus, for patients with HIV infection, the diagnosis of active tuberculosis is more challenging. Clinical suspicion of tuberculosis in a patient known or suspected of being HIV-infected should result in prompt initiation of anti-tuberculosis therapy regardless of sputum staining or radiograph findings. The 1998 CDC recommendations for the treatment of tuberculosis among patients infected with HIV are summarized in Table 2[15]. The treatment of tuberculosis in the HIV-seropositive patient may differ from the standard treatment in the following ways: (i) choice of anti-tubercular regimen and dose adjustments; (ii) duration of treatment (ideally with directly observed therapy); (iii) promotion of antiretroviral therapy; and (iv) monitoring requirements. Due to rapid advances in the management of HIV disease, it is recommended that all patients co-infected with HIV and tuberculosis should be evaluated by a specialist to ensure optimal management.Table 2: Tuberculosis (TB) treatment recommendations for the HIV-seropositive patient.The treatment algorithm begins with establishing the patient's HIV status and whether the patient is on optimal antiretroviral therapy. All patients diagnosed with active tuberculosis should be HIV tested and, if seropositive, evaluated for antiretroviral therapy. It was previously felt that the diagnosis of active tuberculosis should result in the deferral of antiretroviral therapy. Early initiation of antiretroviral therapy is now recommended. While being treated for tuberculosis, the HIV-positive patient not receiving concurrent HIV therapy should be reassessed every 3 months for initiation of antiretroviral therapy. Known or suspected HIV-positive patients should receive prompt initiation of effective anti-tuberculosis therapy. If antiretroviral therapy is not started, the patient can typically receive standard anti-tuberculosis therapy: isoniazid, rifampin, pyrazinamide, and ethambutol. If the patient is to receive simultaneous anti-tuberculosis and antiretroviral therapy, the selected regimens and doses must account for significant drug-drug interactions between the rifamycins (rifampin, rifabutin, rifapentine) and the protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTI). Rifamycins, particularly rifampin, induce the hepatic cytochrome P-450 (CYP450) and reduce the serum levels of protease inhibitors, NNRTI, and other drugs metabolized by the CYP450 system. The CDC generally recommends the substitution of rifabutin, a less potent CYP450 inducer, for rifampin to allow simultaneous use of protease inhibitors and NNRTI. The use of rifampin with protease inhibitors or NNRTI is contraindicated, except in three antiretroviral combinations: (i) the NNRTI efavirenz and two nucleoside reverse transcriptase inhibitors (NRTI); (ii) the protease inhibitor ritonavir and one or more NRTI; and (iii) the combination of ritonavir and saquinavir, either hard-gel or soft-gel capsules [16]. Table 3 lists the recommended anti-tubercular drug doses, depending on frequency of administration and concurrent antiretroviral use.Table 3: Anti-tubercular drug doses.If the HIV-positive patient is already on an effective anti-retroviral regimen at the time of tuberculosis diagnosis, it is desirable to continue the patient on the same antiretroviral regimen with appropriate dose adjustments. If the patient is starting a new antiretroviral regimen, options include: (i) a rifabutin-based regimen with the necessary protease inhibitor or NNRTI dose adjustments; (ii) a non-rifamycin-containing regimen such as isoniazid, streptomycin, pyrazinamide, ethambutol for 2 months, then isoniazid, streptomycin, ethambutol for 7 months; or (iii) a regimen that does not contain a protease inhibitor or NNRTI. Table 4 lists the recommended dose adjustments for rifabutin-based regimens. Given the complexity of these drug interactions, it is recommended that the selection of dual anti-tubercular and antiretroviral therapies be made following consultation with a specialist.Table 4: Protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) dose adjustments with rifabutin.Among the protease inhibitors, ritonavir has the highest potency in inhibiting the CYP450 pathway. With any dose of ritonavir, including low-dose ritonavir 100 mg twice a day, a reduced dose of rifabutin (150 mg two or three times per week) is recommended. According to the 2000 CDC guidelines for the use of rifabutin or rifampin among patients taking protease inhibitors or NNRTI, co-administration of ritonavir with the usual dose of rifampin (600 mg daily or two or three times per week) may be an option but pharmokinetic and clinical data are limited [16]. As previously stated, a patient taking the combination of saquinavir (either the soft-gel or hard-gel capsule) and ritonavir should take the reduced dose of rifabutin (150 mg two or three times per week). The saquinavir-ritonavir combination may possibly be given with the usual dose of rifampin but, again, limited pharmacokinetic and clinical data are available. Saquinavir, as a sole protease inhibitor, is generally not recommended in combination with rifabutin because the serum levels of saquinavir may be decreased as much as 45%. Indinavir, nelfinavir, and amprenavir should not be used in combination with rifampin, but all three protease inhibitors can be administered with a reduced daily dose of rifabutin (150 mg daily) or the usual dose of rifabutin (300 mg two or three times per week). Efavirenz induces CYP450 and accelerates rifamycin metabolism; therefore, efavirenz should be co-administered with an increased dose of rifabutin (450 or 600 mg daily, or 600 mg two or three times per week). According to the recent CDC guidelines, efavirenz may be combined with the usual dose of rifampin (600 mg daily or two or three times per week). The NNRTI nevirapine should typically be given with the usual dose of rifabutin (300 mg daily or two or three times per week). If co-administration of nevirapine with rifampin is clearly indicated, careful monitoring is recommended. The use of delavirdine is contraindicated during the treatment of tuberculosis because the drug levels are markedly decreased with both rifampin and rifabutin. HIV-infected patients have a higher incidence of drug-resistant tuberculosis isolates than non-HIV-infected patients. There have been several reports of increased risk of rifampin resistance among HIV-positive patients [19-21]. Higher rates of drug-resistant tuberculosis in HIV-infected patients may be associated with biological, behavioral, and societal factors including drug malabsorption, non-adherence, nosocomial outbreaks, and inadequate drug therapy in countries with high rates of co-infection. Directly observed therapy, regarded as the best strategy for ensuring adherence and limiting drug-resistant tuberculosis, is recommended for all patients with HIV infection [15]. In a randomized, controlled trial of anti-tuberculosis therapy among HIV-positive patients in Baltimore, Maryland, patients who received supervised therapy for tuberculosis had better survival than those who self-administered therapy [22]. Treatment of drug-resistant tuberculosis involves initiation of a multi-drug regimen tailored to the susceptibility profile of the organism. Due to the diversity of resistance patterns, it is not possible to recommend standardized protocols for therapy. Any regimen should include two or more drugs to which the isolate is susceptible. For HIV-positive patients at risk of MDR-TB, defined as resistance to both isoniazid and rifampin, initial empiric treatment should include second-line tuberculosis drugs to which resistance is uncommon. The 1999 WHO Essential Drug List was to include the following second-line tuberculosis amikacin, kanamycin, capreomycin, cycloserine, acid, and and drug susceptibility testing should be on all tuberculosis isolates and the anti-tuberculosis regimens Although MDR-TB is associated with a high mortality rate especially in resource-poor countries where the detection of drug resistance to months, if at and the second-line drugs are often months is the duration of treatment for pulmonary tuberculosis among HIV-positive patients in the United States a regimen is used [15]. treatment is for patients with a clinical or conversion of sputum cultures from positive to Some experts recommend the use of treatment regimens in all patients with HIV infection, especially among patients with advanced [17]. duration of treatment is clearly recommended in patients with slow clinical or with or HIV-positive individuals with active tuberculosis to be at increased risk of tuberculosis of a 6-month regimen. A trial of isoniazid was among HIV-positive patients in who a 6-month regimen of isoniazid decreased the risk of a of tuberculosis among HIV-positive patients. This not whether these were to M. tuberculosis or both of which have previously been The recommend of isoniazid for HIV-positive patients of tuberculosis therapy. At present, the WHO and the CDC recommend a months of directly observed tuberculosis therapy without Treatment of latent tuberculosis infection in patients with HIV infection It is estimated that 2 people worldwide are infected with latent tuberculosis. Patients with HIV infection are at increased risk of to active disease [2]. In 2000, the and the CDC new guidelines for the diagnosis and treatment of latent tuberculosis infection This public health strategy both prevention by the latent infection before it to active infection and primary prevention by further tuberculosis In addition, the use of active antiretroviral therapy has been to reduce the incidence of tuberculosis among persons with HIV infection The new guidelines recommend targeted of populations and patients at increased risk of tuberculosis infection who from treatment to active for targeted include drug health care of and all patients with HIV Diagnosis of latent tuberculosis infection is on the tuberculin skin new including detection are being developed A has with tuberculin skin testing in are to the diagnostic of this in the United States and in populations with varying degrees of risk for latent tuberculosis. There be two significant of developing tests for the detection of latent M. tuberculosis tests the need for a health service at and their be less than tuberculin skin testing. of latent tuberculosis in an HIV-infected patient can be a diagnostic It has been that the sensitivity of tuberculin skin testing may be in patients with to as well as to and can in persons with HIV infection and of the is associated with higher CD4 cell For these testing is no recommended for the diagnosis of latent tuberculosis. guidelines are to treat latent tuberculosis infection in HIV-infected persons with at high-risk of latent tuberculosis or with recent to a case of active tuberculosis should receive therapy regardless of tuberculin has been the of treatment of latent tuberculosis clinical have a in the risk of to active tuberculosis following months of isoniazid therapy. The optimal duration of isoniazid therapy has also been including the trial of the Tuberculosis and in in the and this or months of isoniazid therapy months of isoniazid therapy reduced the tuberculosis incidence by with for months and 20% for 3 months; however, with months therapy was than for of therapy A recent of isoniazid therapy in that from isoniazid therapy 9 months, with no additional associated with therapy The new and CDC guidelines recommend isoniazid therapy for 9 months (300 mg isoniazid daily mg with months of therapy as a less The to isoniazid therapy include and poor Directly observed therapy has been to adherence but is not important in the treatment of latent tuberculosis has been the of regimens that may adherence and reduce have the of regimens for the treatment of latent tuberculosis in individuals A trial that daily rifampin and pyrazinamide for 2 months was to isoniazid for months for the treatment of latent tuberculosis in HIV-infected persons the of these the new guidelines regimens for the treatment of latent tuberculosis as summarized in Table from their publication rifampin and pyrazinamide for 2 months (600 mg rifampin daily pyrazinamide daily) is the regimen for HIV-infected patients and be for suspected cases of tuberculosis. should be for rifampin in patients receiving protease inhibitors or NNRTI, further is to in the treatment of latent tuberculosis. The same drug-drug interactions and dose adjustments for antiretroviral drugs and rifamycins It is that the also recommends the regimen for individuals the the clinical for this combination have been only in HIV-positive patients. If MDR-TB is the recommended therapy is pyrazinamide and ethambutol or pyrazinamide and a (i.e., or for Treatment for suspected to MDR-TB should be extended to months for HIV-positive American Thoracic Society and Centers for Disease Control and Prevention guidelines for the treatment of latent tuberculosis the use of rifampin pyrazinamide therapy in infected patients has been associated with a rate of patients with resulting from the use of therapy have been to the five of these patients on these CDC and have their 2000 recommendations The (i) that be used with particularly in patients with disease, on or those taking drugs; and (ii) that patients who are treated with be by a health care at and for a of tests and evaluation with a at 8 to treatment therapy with the regimen should be for significant rates of have not been observed in HIV-infected patients treated with this regimen, either in clinical or to the use of the regimen in For HIV-infected patients to persons with active tuberculosis, treatment for latent tuberculosis should be a tuberculin In addition, some experts advocate HIV-infected individuals who in high-risk evaluation for latent tuberculosis treatment should include a careful and and, chest radiograph to exclude active tuberculosis. anti-tubercular drugs in treatment of tuberculosis, particularly for MDR-TB, will on the of new anti-tubercular there are several drugs under that have in M. tuberculosis. In some cases the drug has also in a of tuberculosis, and some have received and Drug for other under include and other and is a rifamycin the serum of which is three times than that of the rifampin The of M. tuberculosis is to or one to that of Given the between and other rifamycin the of over rifampin pharmokinetic In the infected with tuberculosis and in tuberculosis a regimen is less active than a daily regimen, both rifamycins being given at 10 In tuberculosis however, the regimen is significantly less active than the daily regimen In the regimens during the of tuberculosis therapy may provide increased to as well as to health care programs. is an for and other infections that has in M. tuberculosis, to that of and in in a of tuberculosis that at 100 is as as isoniazid at and more than clinical are being to the role of in combination therapy active tuberculosis. and also promising in a of tuberculosis are a class of inhibitors with and The of at 100 is with isoniazid at per an by the and Drug for the treatment of appears to be less active M. tuberculosis than It has been recommended, however, for further at higher is a new to that has been to potent in M. in were also to be to this with of In a administration of this drug at a dose of per led to of disease burden in and with that with isoniazid per and issues in the treatment of tuberculosis in patients with HIV have previously to some of the and issues that the treatment of tuberculosis in resource-poor countries. At the and there may also some important and to effective tuberculosis treatment. A among tuberculosis patients in Tanzania that only of the patients had of the disease and treatment In a recent from people were generally well HIV but tuberculosis of and were to AIDS than tuberculosis. patients with tuberculosis were often as having AIDS. Due to the associated with the that patients with tuberculosis may not or to appropriate These the important impact that the HIV epidemic may have on the public and to tuberculosis. a epidemic of tuberculosis and HIV co-infection in many of the developing world. The increased of tuberculosis and HIV/AIDS and the rise of MDR-TB a health threat to all While significant have been made in developing regimens for the treatment of active and latent tuberculosis, therapy is and second-line drugs are drug resistance is for are the anti-tuberculosis of drugs such as and and the of which may treatment. The optimal use of these drugs in combination therapy is a promising of active In addition, we advocate the of new and tuberculosis drugs that will be made to patients in developing countries.

Current Concepts in the Management of Tuberculosis

BACKGROUND AND OBJECTIVES:There are few reports of cutaneous tuberculosis with immunosuppressed states such as HIV, use of immunosuppressants or malignancy. Diagnosis is thus difficult and despite scientific advances such as polymerase chain reaction, it is frequently missed. Although rare, given its worldwide prevalence and the rising incidence of HIV, it is important for clinicians to recognize the variants and promptly treat the patient.DESIGN AND SETTING:Retrospective study of all cases of cutaneous tuberculosis diagnosed from October 2007 to November 2009 at an outpatient clinic of a tertiary-care hospital in northern India.METHODS:We collected information on the clinical form of disease, histopathology and HIV concurrence rates and looked for differences in presentation between mmunocompetent and immunocompromised states. We also looked for differences and HIV concurrence between immunocompetent and immunocomprised patients. Diagnosis was based on clinical, histopathological and microbiological tests for tuberculosis and a test for HIV.RESULTS:The overall incidence of cutaneous tuberculosis was 0.7% (131 of 18720 outpatients). HIV concurrence was 9.1% (12 cases) of all cutaneous tuberculosis cases. Most common variants seen were scrofuloderma (36.5%), lupus vulgaris (31%), tuberculosis verruca cutis (12.9%), lichen scrofulosorum (11.4%), papulonecrotic tuberculids (3.8%), erythema nodosum (2.2%) and erythema induratum of Bazin (1.5%).CONCLUSIONS:Cutaneous tuberculosis rates were slightly higher in our study than in other studies from India. HIV co-infection rates were similar to those in other studies. Many atypical morphological forms and presentations were observed in HIV co-infected patients. Due to the varied clinical presentations, physician awareness and a high index of suspicion are necessary to diagnose cutaneous forms of tuberculosis.

An Outbreak of Tuberculosis Among Adults With Mental Illness

Strategies to improve tuberculosis case finding in children.

Quantitative C-reactive protein (CRP) in pulmonary tuberculosis.

Tuberculosis (TB), a multisystemic disease with protean presentation, remains a major global health problem. Although concurrent pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) cases are commonly observed clinically, knowledge regarding concurrent PTB-EPTB is limited. Here, a large-scale multicenter observational study conducted in China aimed to study the epidemiology of concurrent PTB-EPTB cases by diagnostically defining TB types and then implementing association rules analysis. The retrospective study was conducted at 21 hospitals in 15 provinces in China and included all inpatients with confirmed TB diagnoses admitted from Jan 2011 to Dec 2017. Association rules analysis was conducted for cases with concurrent PTB and various types of EPTB using the Apriori algorithm. Evaluation of 438,979TB inpatients indicated PTB was the most commonly diagnosed (82.05%) followed by tuberculous pleurisy (23.62%). Concurrent PTB-EPTB was found in 129,422 cases (29.48%) of which tuberculous pleurisy was the most common concurrent EPTB type observed. The multivariable logistic regression models demonstrated that odds ratios of concurrent PTB-EPTB cases varied by gender and age group. For PTB cases with concurrent EPTB, the strongest association was found between PTB and concurrent bronchial tuberculosis (lift = 1.09). For EPTB cases with concurrent PTB, the strongest association was found between pharyngeal/laryngeal tuberculosis and concurrent PTB (lift = 1.11). Confidence and lift values of concurrent PTB-EPTB cases varied with gender and age. Numerous concurrent PTB-EPTB case types were observed, with confidence and lift values varying with gender and age. Clinicians should screen for concurrent PTB-EPTB in order to improve treatment outcomes.

BackgroundSystematic household contact investigation (SHCI) is recommended as an active-case-finding (ACF) strategy to identify individuals at high risk of tuberculosis (TB) infection, in order to enable early detection and treatment. Reluctance to implement SHCI in sub-Saharan African and South African high-burden contexts may stem from uncertainty about the potential yield of this strategy when targeting specific categories of TB index cases. In order to inform and motivate scale-up, this pilot study investigated the effectiveness of SHCI when targeting the World Health Organization’s (WHO) recommended categories of infectious index cases.MethodData were gathered in September and October 2016. Household contacts of infectious TB cases who attended 40 primary health care facilities in Mangaung Metropolitan District were recruited. The categories of TB index cases included 1) children <5 years, 2) HIV co-infected pulmonary TB (PTB) cases (≥5 years), 3) HIV-negative PTB cases (≥5 years), and 4) multidrug-resistant (MDR) TB cases. Contacts were screened for TB symptoms and symptomatic individuals and all children <5 years were referred for clinical evaluation. Data were analysed to establish the yield and factors associated with new TB diagnosis.ResultsOf 259 contacts screened, just under half (47.1%) underwent TB clinical investigation, during which 17 (6.6%) new TB cases were diagnosed, which represents a prevalence rate of 6564 per 100,000 population. Fifteen contacts needed to be screened to detect one new TB case. The proportion of new TB cases was the highest among contacts of HIV-negative PTB index cases (47.9%). The likelihood of TB diagnosis was higher among male contacts (odds ratio [OR]: 4.8; 95% confidence interval [CI]: 1.54–14.97) and those reporting coughing (OR: 4.3; 95% CI: 1.11–16.43).ConclusionThe high yield of new TB observed in this pilot study demonstrates that targeted SHCI may be an effective ACF strategy in Mangaung and similar high-burden settings in South Africa. Targeting different index case categories produced variable yield – the highest among contacts of HIV-negative TB index cases. SHCI among household contacts of all four the WHO-recommended categories of infectious TB index cases – and male and coughing contacts, in particular – should be maximised.

Pleural Tuberculosis in the United States: Incidence and Drug Resistance

Institutional Control Measures for Tuberculosis in the Era of Multiple Drug Resistance: ACCP/ATS Consensus Conference

In this paper we will present an overview of what is known about prevention of HIV associated infections in sub-Saharan Africa. We will focus on primary prophylaxis aiming to prevent first episodes of infections as feasibility and access to secondary prophylaxis cannot be separated from the treatment of opportunistic infections. (excerpt)

Detection of Pulmonary Tuberculosis in Patients With a Normal Chest Radiograph

Evidence‐based consensus on opportunistic infections in inflammatory bowel disease

Tuberculosis (TB)/HIV co-infection represents a major problem in many regions of the world, including Romania. TB is a leading cause of death among people infected with HIV and HIV infection is the most important risk factor for progression from latent to active TB. TB can occur at any stage of HIV disease and its manifestations depend on the severity of immunosuppression. The proportion of extra-pulmonary tuberculosis in HIV infected patients has increased. Aim: to analyze the cases of pulmonary and extrapulmonary TB in HIV-seropositive patients monitored in Third Department of the “Matei Bals” Institute. We performed a retrospective analysis of all HIV infected patients monitored in our clinic from 2000 to 2014 in order to establish the location of TB, the diagnosis methods, the correlation with the immune status and the outcome. 122 patients were retrospectively analyzed; from them, 18 patients were diagnosed with certain, probable or possible TB infection (14.75%). Sex ratio in TB group was M:F=1.57:1 and mean age was 39.7 years old at the moment of TB diagnosis. TB occurs at a variable level of immunosuppression (CD4 count from 6 to 460/cmm) - 4 patients (22.2%) in stage 2 - CD4=200-500/cmm and 14 patients (77.8%) in stage 3 - CD4<200/cmm. Mean CD4 count in TB group was 113.23/cmm vs. 218.33 mean nadir CD4 count in non-TB group. Pleuro-pulmonary TB accounted for only 27.7% of all cases - one pleural effusion and 4 pulmonary TB. In most of cases, TB infection was extrapulmonary (72.3%): 5 cases of meningoencephalitis (27.7%), 3 cases of disseminated TB (16.66%), 2 cases of lymph node TB (11.11%) and 3 cases with unknown location (16.66%). TB was microbiologically confirmed in only 6 cases – 33.33%, 3 by blood culture, 2 by PCR (one from CSF and one from pleural effusion) and 1 by histopathologic exam (lymph node biopsy). In 9 cases TB was probable but without bacteriologic confirmation and in 3 cases TB was possible – prolonged fever with a good outcome under anti-TB medication. Quantiferon TB was performed in only 8 cases – in 6 cases was positive, in one case was negative and in one case was undetermined. Three patients died: one patient because of disseminated TB and two patients because of other HIV-related comorbidities. HIV infected patients developed especially extra-pulmonary TB infection. TB can occur in any stage of HIV infection. Microbiological diagnosis in TB is positive in a small number of cases.