Progressive Primary Tuberculosis Research Articles

Progressive Primary Pulmonary Tuberculosis in Current Times: Are we really heading Towards ‘End of TB’ or Still, Many Miles to go for ‘Dream Come True’?

Tuberculosis is a more prevalent disease and the leading cause of death from an infectious agent in India. Tuberculosis in India accounts for the highest number of cases and deaths annually in the world. In spite of an efficient National tuberculosis control program for five decades, Tuberculosis is still the number one cause of death due to infectious agents in India and one third of total global deaths occurs in India due to this disease. Burden of drug sensitive and drug resistant cases is highest in the south east Asian region with maximum cases in India and China. India has launched a National strategic plan to end TB in 2017 with a target to eliminate TB by 2025. Main theme of the national strategic plan is ‘TB Free India’ with the vision of zero TB disease, zero deaths due to TB and decreasing poverty due to TB. Tuberculosis is an ancient disease and history traced before the evolution of mankind on this planet. Tuberculosis primarily affects the lung and is classified pathologically as primary, post-primary and progressive primary tuberculosis. In this case report, a 62-year male, presented with constitutional symptoms for six-month duration with partial response to medical treatment. He was having low grade fever, cough, shortness of breath, weight loss and anorexia for 6 months. His symptoms were progressive and empirically treated as enteric or typhoid fever for four to five occasions with oral and intravenous antibiotics with steroids with general physicians and family physicians. Additionally, he received empirical treatment as jaundice, viral fever, bronchitis, asthma, and generalised debilitating disease. Relatives brought to our center worsened general health with increased shortness of breath. Clinically he was having bilateral crepitations with decreased breath sounds right lower axillary and infrascapular area. Chest x-ray showed right pleural effusion with miliary opacities bilateral lung field. HRCT thorax showed typical miliary opacities with conglomerated pattern and pleural effusion on the right side of thorax. Pleural fluid analysis revealed exudative effusion with raised ADA level. He was unable to produce sputum, we have done bronchoscopy and BAL evaluation confirmed pulmonary tuberculosis and sensitivity pattern. BAL cytology documented acid-fast bacilli in smear and MTB genome with rifampicin sensitivity in cartridge based nucleic acid amplification test. Treatment initiated with anti-tuberculosis (ATT). We have recorded near complete radiological resolution, bacteriological cure after eight months of ATT with good compliance. More awareness is required regarding symptoms, diagnosis and treatment of tuberculosis to family physicians and general practitioners as the majority of the rural population receives treatment from these health professionals.

Paediatric progressive primary tuberculosis

A previously healthy 13-year-old Japanese girl with a BCG vaccination history and no tuberculosis (TB) exposure history presented to the hospital with mild dyspnea for 1 month and fever for 5 days. Computed tomography showed consolidation with a pleural effusion, obstructed left main bronchus with an air bronchogram, and traction bronchiectasis of the left upper lobe (Fig. 1A, B). No improvement was observed with ampicillin. Computed tomography on day 23 showed a new granular shadow in the right upper lobe (Fig. 1C). Despite a negative interferon-gamma release assay (IGRA) result, the sputum on day 55 was positive for acid-fast bacilli on a ZiehlNeelsen stain and Mycobacterium tuberculosis on polymerase chain reaction. A fourdrug antituberculous regimen was initiated and she recovered rapidly. TB exposure history, positive tuberculin skin test or IGRA, and typical imaging findings are the triad for primary TB diagnosis (Perez-Velez and Marais, 2012; Lewinsohn et al., 2017; Ahmed et al., 2020). In pediatric primary TB, consolidation may be present and can be misdiagnosed as bacterial pneumonia; however, massive consolidation is rare (GriffithRichards et al., 2007). Primary pulmonary TB should be considered in children with lung consolidation that is unresponsive to antibiotics, despite negative IGRA and TB exposure history.

Evaluation of diagnostic components and management of childhood pulmonary tuberculosis: a prospective study from Istanbul, Turkey.

The diagnosis of childhood tuberculosis is difficult and most of the patients are diagnosed clinically. The objective of this study is to reveal the diagnostic and therapeutic components of childhood pulmonary tuberculosis and to analyze the changes that occurred in our country over the years. All patients diagnosed with tuberculosis between 2006 and 2016 were included. Demographic characteristics, diagnostic and treatment outcomes were recorded and patients were followed up prospectively. A total of 492 patients were included in the study. 97% had Bacillus Calmette-Guerin vaccine, 36% were diagnosed with microbiologically-confirmed tuberculosis and 64% were diagnosed with clinically-proven tuberculosis. 94% of the patients had symptoms consistent with tuberculosis, all patients had radiologic findings, 74% had a history of tuberculosis contact and 63% had tuberculin skin test positivity. The diagnoses included primary tuberculosis in 62%, secondary tuberculosis in 21%, progressive primary tuberculosis in 13% and miliary tuberculosis in 4%. 48% of the patients received a treatment regimen containing three drugs as the initial treatment, and drug-related side effects developed in 12%. Isoniazid resistance was detected in 13% of the patients and rifampicin resistance was detected in 8%. None of the patients died due to tuberculosis. In the last 50 years in Turkey, the rates of Bacillus Calmette-Guerin vaccination and diagnosis of tuberculosis cases have increased and the mortality rates have decreased over the years. Our study is one of the few prospective studies and revealed the differences between the recent data and the past 50 years in childhood tuberculosis in Turkey.

Differential Immunogenicity and Protective Efficacy Elicited by MTO- and DMT-Adjuvanted CMFO Subunit Vaccines against Mycobacterium tuberculosis Infection.

Tuberculosis (TB) remains a major and global problem of public health. An effective TB subunit vaccine is urgently needed. Proper selection of the delivery system for the vaccine is crucial for inducing an appropriate immune response tailored to control the target pathogen. In this study, we compared the immunogenicity and protective efficacy of CMFO subunit vaccines against primary progressive TB in two different adjuvant systems: the MTO oil-in-water (O/W) emulsion composed of monophosphoryl lipid A (MPL), trehalose-6,60-dibehenate (TDB), and oil in water emulsion MF59 and the DMT liposome containing dimethyldioctadecylammonium bromide (DDA), monophosphoryl lipid A (MPL), and trehalose-6,60-dibehenate (TDB). Our results demonstrated that the DMT-adjuvanted CMFO could confer more significant protection against M. tuberculosis infection than the CMFO/MTO did in mice. In particular, the adjuvant DMT showed a stronger ability than the O/W emulsion to adjuvant CMFO subunit vaccine and enhanced protection, attributed to elicit Th1-biased responses, strong Th1/Th17 cytokine responses, and IFN-γ+ or IL-2+ T cell responses. Therefore, our findings demonstrate that the liposome delivery system shows more effectiveness to adjuvant TB subunit vaccine than O/W emulsion and highlight the importance of adjuvant formulation for the better efficacy of a protein vaccine.

Platelets Restrict the Oxidative Burst in Phagocytes and Facilitate Primary Progressive Tuberculosis.

Rationale: Platelets are generated in the capillaries of the lung, control hemostasis, and display immunological functions. Tuberculosis primarily affects the lung, and patients show platelet changes and hemoptysis. A role of platelets in immunopathology of pulmonary tuberculosis requires careful assessment.Objectives: To identify the dynamics and interaction partners of platelets in the respiratory tissue and establish their impact on the outcome of pulmonary tuberculosis.Methods: Investigations were primarily performed in murine models of primary progressive pulmonary tuberculosis, by analysis of mouse strains with variable susceptibility to Mycobacterium tuberculosis infection using platelet depletion and delivery of antiplatelet drugs.Measurements and Main Results: Platelets were present at the site of infection and formed aggregates with different myeloid subsets during experimental tuberculosis. Such aggregates were also detected in patients with tuberculosis. Platelets were detrimental during the early phase of infection, and this effect was uncoupled from their canonical activation. Platelets left lung cell dynamics and patterns of antimycobacterial T-cell responses unchanged but hampered antimicrobial defense by restricting production of reactive oxygen species in lung-residing myeloid cells.Conclusions: Platelets are detrimental in primary progressive pulmonary tuberculosis, orchestrate lung immunity by modulating innate immune responsiveness, and may be amenable to new interventions for this deadly disease.

IFN-\u03b3-independent immune markers of Mycobacterium tuberculosis exposure

Exposure to Mycobacterium tuberculosis (Mtb) results in heterogeneous clinical outcomes including primary progressive tuberculosis and latent Mtb infection (LTBI). Mtb infection is identified using the tuberculin skin test and interferon-γ (IFN-γ) release assay IGRA, and a positive result may prompt chemoprophylaxis to prevent progression to tuberculosis. In the present study, we report on a cohort of Ugandan individuals who were household contacts of patients with TB. These individuals were highly exposed to Mtb but tested negative by IFN-γ release assay and tuberculin skin test, ‘resisting’ development of classic LTBI. We show that ‘resisters’ possess IgM, class-switched IgG antibody responses and non-IFN-γ T cell responses to the Mtb-specific proteins ESAT6 and CFP10, immunologic evidence of exposure to Mtb. Compared to subjects with classic LTBI, ‘resisters’ display enhanced antibody avidity and distinct Mtb-specific IgG Fc profiles. These data reveal a distinctive adaptive immune profile among Mtb-exposed subjects, supporting an expanded definition of the host response to Mtb exposure, with implications for public health and the design of clinical trials.

Tuberculin skin test conversion and primary progressive tuberculosis disease in the first 5 years of life: a birth cohort study from Cape Town, South Africa

SummaryBackgroundTuberculosis is a leading cause of global childhood mortality. However, the epidemiology and burden of tuberculosis in infancy is not well understood. We aimed to investigate tuberculin skin test conversion and tuberculosis in the Drakenstein Child Health study, a South African birth cohort in a community in which tuberculosis incidence is hyperendemic.MethodsIn this prospective birth cohort study, we enrolled pregnant women older than 18 years who were between 20 and 28 weeks' gestation and who were attending antenatal care in a peri-urban, impoverished South African setting. We followed up their children for tuberculosis from birth until April 1, 2017, or age 5 years. All children received BCG vaccination at birth. Tuberculin skin tests were administered to children at 6, 12, 24, 36, 48, and 60 months of age, and at the time of a lower respiratory tract infection. An induration reaction of 10 mm or more was considered to be a tuberculin skin test conversion. To prevent boosting, we censored children with a reactive, negative tuberculin skin test.FindingsAmong 915 mother–child pairs (201 [22%] HIV-positive mothers and two [<1%] HIV-positive children), 147 (16%) children had tuberculin skin test conversion, with increasing cumulative hazard with age (0·08 at 6 months, 0·17 at 12 months, 0·22 at 24 months, and 0·37 at age 36 months). For every 100 child-years, the incidence was 11·8 (95% CI 10·0–13·8) for tuberculin skin test conversion, 2·9 (2·4–3·7) for all diagnosed tuberculosis, and 0·7 (0·4–1·0) for microbiologically confirmed tuberculosis. Isoniazid preventive therapy was effective in averting disease progression (adjusted hazard ratio 0·22, 95% CI 0·08–0·63; p<0·0001). Children with a lower respiratory tract infection were significantly more likely to also have tuberculosis than were those without one (2·27, 1·42–3·62; p<0·0001).InterpretationGreater focus should be placed on the first years of life as a period of high burden of transmission and clinical expression of tuberculosis infection and disease. Multifaceted interventions, such as isoniazid preventive therapy and tuberculosis screening of infants with LRTIs, beginning early in life, are needed in high-burden settings.FundingBill & Melinda Gates Foundation, Medical Research Council South Africa, and National Research Foundation South Africa.

A Multistage Subunit Vaccine Effectively Protects Mice Against Primary Progressive Tuberculosis, Latency and Reactivation

Adult tuberculosis (TB) is the main cause of TB epidemic and death. The infection results mainly by endogenous reactivation of latent TB infection and secondarily transmitted by exogenous infection. There is no vaccine for adult TB. To this end, we first chose antigens from a potential antigenic reservoir. The antigens strongly recognized T cells from latent and active TB infections that responded to antigens expressed by Mycobacterium tuberculosis cultured under different metabolic states. Fusions of single-stage polyprotein CTT3H, two-stage polyprotein A1D4, and multistage CMFO were constructed. C57BL/6 mice vaccinated with DMT adjuvant ed CMFO (CMFO-DMT) were protected more significantly than by CTT3H-DMT, and efficacy was similar to that of the only licensed vaccine, Bacillus Calmette–Guérin (BCG) and A1D4-DMT in the M. tuberculosis primary infection model. In the setting of BCG priming and latent TB infection, M. tuberculosis in the lung and spleen was eliminated more effectively in mice boosted with CMFO-DMT rather than with BCG, A1D4-DMT, or CTT3H-DMT. In particular, sterile immunity was only conferred by CMFO-DMT, which was associated with expedited homing of interferon-gamma+CD4+ TEM and interleukin-2+ TCM cells from the spleen to the infected lung. CMFO-DMT represents a promising candidate to prevent the occurrence of adult TB through both prophylactic and therapeutic methods, and warrants assessment in preclinical and clinical trials.

English

INTRODUCTION: Progressive primary pulmonary tuberculosis is rare in infancy and may often be confused with bacterial pneumonia or congenital anomalies. However it may be an important cause of morbidity and mortality in a highly endemic country like India. CASE REPORT: A 3 month old female child presented with fever, cough and respiratory distress for past 1 month. She was treated for Pneumonia with antibiotics for 15 days by a local practitioner, with no improvement and so was referred to our Centre. She was BCG vaccinated and there was no history of contact with tuberculosis patient. Chest X-Ray PA view revealed bilateral extensive infiltrates suggestive of Bronchopneumonia. AFB staining of gastric lavage was positive. CSF analysis and USG abdomen were within normal limits. A provisional diagnosis of progressive primary pulmonary tuberculosis was made and she was started on anti-tuberculosis treatment, to which she responded dramatically and repeat AFB stain of gastric lavage was negative. CONCLUSION: A diagnosis of Pulmonary TB should be suspected in infants with non-resolving pneumonia, even in BCG vaccinated infants and without

Endobronchial Tubercolosis: a peculiar feature of TB often underdiagnosed

Endobronchial Tuberculosis (EBTB) is a particular form of TB non easily recognizable, often dangerous for its consequences and potentially a source of spread of infection in the community. Also its definition doesn't find a unanimity. In fact it has been defined as “tuberculous infection of the tracheo bronchial tree with microbial and histopathological evidence” [1] or a” complication of progressive primary Tuberculosis” [2] or, more simply, a “special form of pulmonary Tuberculosis” [3]. It should be stressed that the presence of signs and symptoms qualifies it as a particular expression of a tubercular disease rather than a tubercular infection. Another point of discussion might regard the clinical role of EBTB considering that in the strict sense of a correct classification of TB it might be allocated among the extrapulmonary forms, therefore subjected to diagnostic problems arising from the variability of their clinical manifestations, even though the close continuity with the remaining part of the respiratory system can better draw the attention of the clinicians in comparison with other extrapulmonary localizations. Despite this more favourable position a delay in the diagnosis may be observed with important and seldom severe consequences.

Acute respiratory distress during paradoxical reaction to antituberculous therapy in an 8-month-old child

Paradoxical reaction during antituberculosis treatment (ATT) is commonly seen as tuberculous lymphadenitis of peripheral lymph node, cerebral tuberculomas, pulmonary infiltrates, and pleural disease. This phenomenon is more commonly associated with extrapulmonary tuberculosis and disseminated tuberculosis. Respiratory distress, as presentation of paradoxical reaction, is rare. We report an 8-month-old child with primary progressive tuberculosis without mediastinal adenopathy, who developed paradoxical reaction with extensive mediastinal adenopathy within 15 days of ATT and presented with severe respiratory distress. The child responded to short course of high-dose steroids.

Primary Progressive Tuberculosis in an Adolescent with Presentation of Clubbing

Primary Progressive Tuberculosis in an Adolescent with Presentation of Clubbing

Progressive primary pulmonary tuberculosis presenting as the sudden unexpected death in infancy: A case report

The classification of an unexpected infant death as the sudden infant death syndrome (SIDS) depends upon a complete autopsy and death scene investigation to exclude known causes of death. Here we report the death of a 4-month-old infant in a tuberculosis endemic area that presented as a sudden unexpected death in infancy (SUDI) with no apparent explanation based on the death scene characteristics. The autopsy, however, revealed progressive primary pulmonary tuberculosis with intrathoracicadenopathy, compression of the tracheobronchial tree and miliary lesions in the liver. This case underscores the clinical difficulties in the diagnosis of infantile tuberculosis, as well as the possibility of sudden death as part of its protean manifestations. The pathology and clinical progression of tuberculosis in infants differ from older children and adults due to the immature immune response in infants. This case dramatically highlights the need for complete autopsies in all sudden and unexpected infant deaths, as well as the public health issues in a sentinel infant tuberculosis diagnosis.

Clinical manifestations of tuberculosis in children

The natural history and clinical manifestations of tuberculosis in children differ significantly from those of the disease seen in adults. The two main factors determining the risk of progression to disease are patient age and immune status. Neonates have the highest risk of progression to disease, and in infancy miliary and meningeal involvement is common. Children from 5 to 10 years of age are less likely to develop disease than other age groups, and adolescent patients can present with progressive primary tuberculosis or cavitary disease. Immunocompromised patients are more likely both to progress to tuberculous disease and to have extrapulmonary manifestations; diagnostic tests are also of lower yield in this population. The most common sites of disease in children are intrathoracic disease and superficial lymphadenopathy. Clinical manifestations are often due to a profound inflammatory response to a relatively low burden of organisms. This is reflected in the low yield of diagnostic tests; consequently, the diagnosis of tuberculosis is often based upon a positive skin test, epidemiological information, and compatible clinical and radiographic presentation.

Tuberculosis primaria progresiva con afectación endobronquial. Aportación de la TC multicorte

To assess computed tomography (CT) imaging findings in progressive primary tuberculosis and to determine the use of the multislice images obtained. We report the case of a 37-day-old infant admitted to hospital because of persistent fever despite antimicrobial therapy. Thoracic X-ray and multislice helical CT (CT Light speed i1.6 GE) were performed with 3-dimensional and virtual endoscopy reconstructions. CT showed mediastinal and hilar necrotic lymph nodes, pulmonary parenchymal involvement with miliary pattern, and multiple cavitated consolidations. Endobronchial involvement was clearly visualized by virtual endoscopy and was confirmed by fiberoptic bronchoscopy. Virtual endoscopy is a new, less invasive alternative radiological technique to fiberoptic bronchoscopy that may influence the management of patients with tuberculosis with endobronchial involvement.

Cytokine profile during latent and slowly progressive primary tuberculosis: a possible role for interleukin-15 in mediating clinical disease

Recently, mouse models for latent (LTB) and slowly progressive primary tuberculosis (SPTB) have been established. However, cytokine profiles during the two models are not well established. Using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) we studied the expression levels of interleukin (IL)-2, IL-4, IL-10, IL-12, IL-15, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha during the course of LTB and SPTB in the lungs and spleens of B6D2F1Bom mice infected with the H37Rv strain of Mycobacterium tuberculosis (Mtb). The results show that, except for IL-4, cytokine expression levels were significantly higher during SPTB than LTB in both the lungs and spleens. During LTB, all the cytokines (except IL-2 in the lungs) had higher expression levels during the initial period of infection both in the lungs and spleens. During SPTB, the expression levels of IL-15 increased significantly from phases 1 to 3 in the lungs. The expression levels of IL-10, IL-12 and IFN-gamma increased significantly from 2 to 3 in the lungs. IL-10 and IL-15 increased significantly from phases 2 to 3, whereas that of TNF-alpha decreased significantly and progressively from phases 1 to 3 in the spleens. Over-expression of proinflammatory cytokines during active disease has been well documented, but factor(s) underlying such over-expression is not known. In the present study, there was a progressive and significant increase in the expression levels of IL-15, together with Th1 cytokines (IL-12 and IFN-gamma) during SPTB but a significant decrease during LTB. IL-15 is known to up-regulate the production of proinflammatory cytokines, IL-1beta, IL-8, IL-12, IL-17, IFN-gamma and TNF-alpha and has an inhibitory effect on activation-induced cell death. IL-15 is known to be involved in many proinflammatory disease states such as rheumatoid arthritis, sarcoidosis, inflammatory bowel diseases, autoimmune diabetes, etc. Our results, together with the above observations, suggest that IL-15 may play an important role in mediating active disease during Mtb infection.

Extensive unilobar primary pulmonary tuberculosis in an infant: A diagnostic dilemma

An 11-month old boy presented with frequent episodes of fever and cough over the past 6 months. Investigations revealed a large space-occupying lesion in the upper lobe of the left lung, the remaining lung fields being clear. There was no history of contact with tuberculosis and the tuberculin test was negative. A CT scan of the chest suggested the presence of a pulmonary sequestration in the upper lobe of the left lung. Surgical excision of the affected lobe was performed and histopathological examination of the excised lobe revealed extensive tuberculosis with caseous necrosis. The presentation of progressive primary tuberculosis in infants is discussed along with the diagnostic difficulties in cases with an atypical presentation.

In situ expression of CD40, CD40L (CD154), IL-12, TNF-alpha, IFN-gamma and TGF-beta1 in murine lungs during slowly progressive primary tuberculosis.

The distribution and expression of CD40, its ligand CD40L (154) and related cytokines interleukin-12 (IL-12), tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and transforming growth factor-beta1 (TGF-beta1) were studied in the lungs of B6D2F1 hybrid mice during slowly progressive primary tuberculosis (TB) by immunohistochemistry. CD40 and CD40L are implicated in cell-mediated immunity (CMI) causing activation or apoptosis of infected cells. The phenomenon of apoptosis is associated with Mycobacterium tuberculosis survival. In this study, using frozen lung sections (n = 33), our results showed increased CD40, IL-12 and TGF-beta1 expression in macrophages with progression of disease. High percentages of mycobacterial antigens (M.Ags), CD40L and IFN-gamma expression were maintained throughout infection, and TNF-alpha-expressing cells were decreased. In lymphocytes, the percentage of IFN-gamma-positive cells was increased, but CD40L and IL-12 were maintained with the progression of disease. M.Ags, CD40 and CD40L were expressed in the same areas of the lesions. We conclude that changes in the expression of CD40-CD40L and cytokines associated with M. tuberculosis infection favour the hypothesis that M. tuberculosis causes resistance of host cells to apoptosis causing perpetuation of infection.

In Situ Expression of Cytokines and Cellular Phenotypes in the Lungs of Mice with Slowly Progressive Primary Tuberculosis

The cellular phenotypes and the expression of cytokines were studied in the lungs of mice, using immunohistochemistry, during different phases of slowly progressive primary murine tuberculosis infection. During the first phase the small focal lesions in healthy mice contained predominantly interleukin-2 (IL-2)-expressing cells. A small number of tumour necrosis factor-alpha (TNF-alpha)-, monocyte chemoattractant protein-1 (MCP-1)- and IL-10-expressing cells were also present. IL-4-expressing cells were not detected. During the second phase the mice became unwell, but the bacterial counts and the size of focal lesions stabilized. IL-4-expressing cells appeared. The IL-10-, TNF-alpha- and MCP-1-expressing cells increased in number. On progression to phase three, the mice became seriously unwell and died rapidly. The inflammation spread to approximately 80% of the lung parenchyma. There was a marked increase in the number of IL-10-expressing cells. Expression of other cytokines was similar to that observed in the second phase. In the lesions, 3-6% of the macrophages (Mphi) containing mycobacterial antigens expressed high levels of IL-10 and TNF-alpha. The absolute numbers of CD3-, CD4- and CD11b-expressing cells in the lesions increased with the progression of infection. The numbers of CD8+ cells were reduced in the last phase of infection. The kinetics of T-lymphocyte subsets and the pattern of cytokine expression changed with the type and degree of tissue injury. The small number of Mphi with a heavy load of mycobacterial antigens may be the cause of this disturbance in cytokine balance, thus leading to progression of inflammation.

Diversity of lung and spleen immune responses in mice with slowly progressive primary tuberculosis.

The aim of the present study was to assess the compartmentalized immune response, in terms of cytokine secretion and cell activation, in lungs and spleens of mice with slowly progressive primary tuberculosis. Immunocyte populations from both organs were isolated and stimulated with concanavalin A, purified protein derivatives and MPT 59. Production of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) was measured using an enzyme-linked immunosorbent assay, and cell activation was measured using a tetrazolium colorimetric assay. The IFN-gamma and IL-4 levels in the supernatants of Mycobacterium tuberculosis antigen (Ag)-stimulated lung immunocytes from infected mice were higher than the levels from uninfected mice. However, only IL-4 levels were raised in the supernatants of Ag-stimulated spleen immunocytes from infected mice. Spontaneous and Ag-stimulated immunocyte activation was lower only in the lungs of infected mice compared with uninfected mice. The level of lung immunocyte activation was inversely associated with the extent of gross pulmonary pathology. In conclusion, cytokine secretion and cell activation were different between lungs and spleens in slowly progressive primary murine tuberculosis. Cytokine diversity may explain the confinement of tuberculous lesions in the lungs and the absence of lesions in the spleens of mice with slowly progressive tuberculosis.