Tuberculosis Mimics

by

Dr.Sandeep Singhal

TUBERCULOSIS• Tuberculosis (TB), which is caused by bacteria of the Mycobacterium

tuberculosis complex, is one of the oldest diseases known to affect humans and a major cause of death worldwide.

• M. tuberculosis complex, which comprises M. tuberculosis M. bovis - transmitted by unpasteurized milk M. caprae M. africanum M. microti (the “vole” bacillus, a less virulent) M. pinnipedii ( infecting seals and sea lions ) M. mungi (isolated from banded mongooses ) M. orygis M. canetti

Morphology of M.tuberculosis

• M. tuberculosis is a rod-shaped, non-spore-forming, acid fast, noncapsulated, non motile, thin aerobic bacterium measuring 0.5 μm by 3 μm.

• Robert Koch isolated it.• Ziehl neelsen staining • Culture:Lowenstein Jensen medium n

colonies- dry, rough,buff coloured,raised,with wrinkled surface

TRANSMISSION• droplet nuclei• coughing, sneezing, or speaking• 3000 infectious nuclei per cough.

• Factors favouring the transmission:

1) Crowding in poorly ventilated rooms2) HIV co-infection3) Malnutrition 4) Diabetes5) Increasing use of

immunosuppressive drugs

Pathophysiology

• mycobacteria reach the pulmonary alveoli• alveolar macrophages--phagosome --

lysosome• Phagocytosis: phagolysosome.• However, M. tuberculosis has a thick, waxy

mycolic acid capsule that protects it from these toxic substances. M. tuberculosis is able to reproduce inside it

Pathophysiology• A complex series of events is generated by the bacterial cell-

wall lipoglycan lipoarabinomannan (ManLAM).• ManLAM inhibits the intracellular increase of Ca2+. Thus,

the Ca2+/calmodulin pathway (leading to phagosome–lysosome fusion) is impaired, and the bacilli survive within the phagosomes.

• The M. tuberculosis phagosome has been found to inhibit the production of phosphatidylinositol 3- phosphate (PI3P)..

• If the bacilli are successful in arresting phagosome

maturation, then replication begins and the macrophage eventually ruptures and releases its bacillary content

1.Primary tuberculosis• primary site -"Ghon

focus”• Ghon’s complex• Ranke’s complex

• Simon focus-bloodstream

• Bacillemia- rupture into draining LN, blood vessel

2.Secondary (Postprimary) TB• reactivation or secondary TB• a/w decreased immune status• result from endogenous reactivation of distant

LTBI or reinfection.• location- apical and posterior segments of the

upper lobe• small infiltrates ,fibrosis, extensive cavitary

disease.• bronchogenic spread - satellite lesions within the

lungs that undergo cavitation – “TREE IN BUD” app on CT

• Lesions seen in secondary TB:

1. Puhl’s lesion- supraclavicular2. Assman focus- infraclavicular3. Rich focus- brain cortex4. weigert’s focus- pulmonary vein5. Simond’s focus- liver

Clinical features

Classic clinical features associated with active pulmonary TB are as follows:

CoughWeight loss/anorexiaFeverNight sweatsHemoptysisChest painFatigue

Extrapulmonary TB • peripheral lymphadenopathy,• Gastrointestinal TB• CNS TB,• miliary TB,• skeletal TB, • Genitourinary TB,• Pericardial TB,• Cutaneous TB,• Ophthalmic TB,• ENT

LAB DIAGNOSIS

• Radiography:A)Chest X-ray: upper lobe infiltrates with cavities

• Microscopic examination: sputum smear or of tissue , BAL –AFB (ZN stain), culture

• Nucleic Acid Amplification Test assays used organisms may be present in amounts too small to be seen by routine staining techniques :GeneXpert MTB RIF assay - <2 hr

• Drug susceptibility test

• Serologic – ADA , IFN Ꝩ levels

• Tuberculin skin test – PPD intradermal – LTBI

• IGRA- measure response of recirculatory memory T cells in response to stimulation with specific antigens: ESAT-6, CFP-10,TB 7.7

1)Quantiferon Gold -diagnosis of latent TB. 2)EnzymeLinked Immunospot Assay (ELISPOT)

• These newer diagnostic modalities – imaging and advanced molecular techniques facilitating the accurate diagnosis of TB.

• Hallmark is demonstration of caseating granuloma and microbial culture.

• Because ,there are many conditions which mimic the clinical profile, radiological features, have noncaseating granulomas but ARE NOT TB

• These are “TB mimics” and necessary to differentiate these conditions for correct diagnosis and proper management as many of them warrant aggressive immunosupressive therapy

TB MIMICS• Nontubercular mycobacterial infection• Histoplasmosis• Coccidioidomycosis• Blastomycosis• Aspergillosis• Nocardiosis• Silicosis• Sarcoidosis• Wegener granulomatosis• Crohn’s disease• Malignancies- lymphoma, ovarian cancer, squamous cell

carcinoma of oral cavity, small cell ca of lung

NTM/MOTT• Found in soil,natural and tap water, dust, animals and

food• Runyon’s classification:1. Photochromogens – M.kansasii,M.simiae2. Scotochromogens - M.scrofulacaeum, M.gordonae3. Nonphotochromogens-avium,intracellulare, xenopi4. Rapid growers- chelonei, fortuitum

• Commonly occurs in pts with pre-existing lung pathology• Causes localised cervical lymhadenitis and pulmonary

disease (infiltrations and cavities) similar to TB and also resemble radiologically ,also sputum shows AFB

GROWTH characters MTB NTB

Rate of growth slow Slow or rapid

temperature 37◦c 25 - 45◦c

on LJ Medium eugonic Dysgonic

colonies Dry, rough,buff coloured ,difficult to emulsify

Dry, yellow-orange,creamy, easily emusifiable

In presence of p-nitrobenzoic acid

No Yes

BIOCHEMICAL REACTION:

1) Niacin test + -

2) Nitrate reduction test + -

• Treatment :

1.M.kansasii- R +E × 15 - 24 months2.M.avium complex- R + E × 2yrs + macrolide3. M.malonese- R + E × 2yrs 4.M.xenopi- R + E × 2yrs

HISTOPLASMOSIS

Histoplasma capsulatum

Small (2–5 nm) narrow budding yeast forms (Grocott's methenamine silver stain)

Etiology and Epidemiology • Thermal, dimorphic fungus that exist as microconidia and macroconidia

• Most prevalent endemic mycosis in North America

• Most prevalent in Mississippi and Ohio valleys

• This geographic pattern is due to humid and acidic nature of soil

• Soil enriched with bird and bat droppings promotes growth and sporulation of histoplasma

• Spelunking, excavation, cleaning of chicken coops, demolition and remodeling of old buildings are activities with high level of exposure

Pathogenesis• Inhaled microconidia reach alveoli - phagocytosed by

alveolar macrophages-- transform into yeast forms. Transformation is a requisite for pathogenesis

• Yeasts replicate---utilize the macrophage’s phagosome as a vehicle to translocate to local draining lymph nodes- spread hematogeneously through RES.

• Histoplasma specific cellular immunity develops in immunocompetent at 2 weeks.

• In immunocompotent hosts, macrophages, lymphocytes, and epithelial cells organize and form granulomas that contain the organism, which typically fibrose and calcify

Manifestations in Immunocompetent Host:• Majority -asymptomatic • Some – pulmonary disease resemble TB• Radiogically- upper lobe infiltrates with hilar/mediastinal adenopathy with

focal calcifications

Manifestations in Immunocompromised Host:• underlying cellular immunity deficiency -develop progressive

disseminated histoplasmosis (PDH)• PDH– multiple organs- m/c bone marrow, spleen ,liver, adrenal glands

and mucocutaneous membranes

• Common manifestations: weight loss, fever, hepatosplenomegaly, meningitis or focal brain lesions, oral mucosal ulcerations, GI ulcers, adrenal insufficiency

• More severe manifestations: respiratory failure, shock, coagulopathy, and MOF

• It can be misdiagnosed as TB and unresponsiveness to anti-TB Rx compels to revise the diagnosis

• DIAGNOSIS:1)Fungal culture – gold std but take a month2)Fungal stains of cytopathology or biopsy materials3)Detection of Histoplasma antigen in body fluids

• TREATMENT: liposomal AmB, itraconazole1) Acute pulmonary:Lipid AmB (3–5 mg/kg per day) ± glucocorticoids for 1–2 weeks; then itraconazole (200 mg bid) for 12 weeks.2) Chronic/cavitary pulmonary( seen in smokers): Itraconazole (200 mg qd or bid) for at least 12 months3) Progressive disseminated: Lipid AmB (3–5 mg/kg per day) for 1–2 weeks; then itraconazole (200 mg bid) for at least 12 months4) Central nervous system:Liposomal AmB (5 mg/ kg per day) for 4–6 weeks; then itraconazole (200 mg bid or tid) for at least 12 months.

Blastomycosis

• etiological agent: Blastomyces dermatitidis, a soil inhabiting dimorphic fungus.

• Blastomycosis is a chronic granulomatous and suppurative disease having a primarypulmonary stage that is frequently followed by dissemination to other body sites,chiefly the skin and bone• Distribution: North America• Pathophysiology same as histoplasmosis

• most commonly presents as acute or chronic pneumonia that has been refractory to therapy with antibacterial drugs.

• Chest xray – nodular shadows and cavities.• Skin disease is the m/c extrapulmonary manifestation Two types of skin lesions occur: verrucous (more common) and ulcerative.• DIAGNOSIS :1)Definitive-- Sabouraud dextrose agar, with or without chloramphenicol. B.dermatitidis is generally visible in 5–10 days but may require incubation for up to 30 days if only a few organisms are present in the specimen. 2)A presumptive - microscopic examination of wet preps of sputum in pneumonia or of skin-lesion scrapings.3)Serologic testing for antibodies to B. dermatitidis -complement fixation, immunodiffusion, or enzyme immunoassay.4) A Blastomyces antigen assay - useful for monitoring of patients during therapy or for early detection of relapse.5)Chemiluminescent DNA probes confirm identification of B. dermatitidis once growth has been detected in culture.

Treatment: • Itraconazole is the agent of choice for immunocompetent

patients with mild to moderate pulmonary or non-CNS extrapulmonary disease for 6–12 months.

• Amphotericin B (AmB) -initial treatment for patients severely immunocompromised, life-threatening disease or CNS disease, or disease progresses during treatment with itraconazole.

• Fluconazole, because of its excellent penetration of the CNS, is

useful in the treatment of patients with brain abscess or meningitis after an initial course of AmB.

• Voriconazole & posiconazole- refractory blastomycosis

Coccidiodomycosis

• caused by Coccidioides immitis, a dimorphic fungus that grows as a mold in the soil.

• The mold forms arthroconidia within the hypha, a type of conidia formation known as enteroarthric development

• Measuring 2 by 5 μm, arthroconidia∼

• Their small size allows them to evade initial mechanical mucosal defences and reach deep into the bronchial tree

• most commonly found in the deserts of the southwestern United States and Central and South America.

• 60% are completely asymptomatic, and the remaining 40% have symptoms that are related principally to pulmonary infection – mild influenza like fever (known as valley fever) to severe pneumonia

• Disseminate- CNS,bones and skin

Cutaneous: Erythema nodosum— typically over the lower extremities or erythema multiforme usually in a necklace distribution.

Diagnosis:• peripheral-blood eosinophilia, hilar or mediastinal adenopathy on

radiographic imaging, marked fatigue, and failure to improve with antibiotic therapy

• Microscopic ex: 1)Coccidioides grows within 3–7 days at 37°C on a variety of artificial media, including blood agar, SDA2) Gomori methenamine silver staining reveals spherules

• Serology: tube-precipitin ,complement-fixation assays, immunodiffusion ,enzyme immunoassay to detect IgM and IgG antibodies

• Antigen level assays

Treatment: antifungal

Aspergillosis

• ETIOLOGY: Genus Aspergillus – worldwide distribution

• most commonly growing in decomposing plant materials (i.e., compost) and in bedding.

• Aspergilli are found in indoor and outdoor air, on surfaces, and in water from surface reservoirs.

• hyaline (nonpigmented), septate hyphae, dichomotous branching( at angle 45) mold produces vast numbers of conidia (spores) on stalks above the surface of mycelial growth.

• Aspergillus fumigatus :most commonly isolated

speciesThermophilic species (Growth at 40° C and above) , angioinvasive other- A.niger,A.flavus,A.terreus, A.nidulans

• Risk factors- neutropenia, steroid therapy, diabetes, pre-existing lung pathology, immunosuppressive therapy

• Affects lung in following ways:1.asthma- type 1 (atopic)2.ABPA-Commonly affects people with asthma and cystic fibrosis patients, expectorate mucous plugs containing fungal hyphae3.Aspergilloma- fungus ball within pre-existing cavity(crescent sign)4.Invasive:immunocompromised,disseminate to other organs-brain ,kidney, heart5.Extrinsic allergic alveolitis(malt worker’s lung)

• Diagnosis:1)Microscopy -Grocott’s methanamine silver stain (GMS) , culture on SDA without cycloheximide at 25c Colonies :- 1-2 days velvety to powdery surface & colouredA.fumigatus- green, A.flavus- golden-yellow, A.niger- black

2)Biopsy of the lungs – H&E stained – characteristic hyphae3)Autopsy Findings of the lungs : Dilated bronchioles ,Alveolar septae showed congested vessels,Edema and hemorrhage

4) Aspergillus antigen test relies on detection of galactomannan release from Aspergillus organisms during growth5) elevated total and specific serum IgE levels 6)CXR n CT chest- halo sign

• Treatment:1. for chronic and allergic forms of aspergillosis :Itraconazole

preferred. Voriconazole or posaconazole can be substituted when failure, emergence of resistance, or adverse events occur.

2. for invasive aspergillosis- voriconazole3. Surgical treatment – - fungal ball of the sinus and single aspergillomas, - invasive aspergillosis involving bone, heart valve, sinuses, proximal areas of the lung; brain abscess; keratitis; and endophthalmitis.• In allergic fungal sinusitis, removal of abnormal mucus and

polyps, with local and occasionally systemic glucocorticoid treatment

• Bronchial artery embolization is preferred for problematic hemoptysis.

Nocardiosis

• caused by aerobic actinomycetes of genus Nocardia.• resides in soil, contributing to the decay of organic matter.• Nocardia infections mostly occurring in immuno-compromised patients

with <250 CD4+ T lymphocytes .• branching, beaded, gram-positive filaments 1 μm wide and up to 50 μm long . • Most nocardiae are acid-fast in direct smears if a weak acid is used for decolorization (e.g., in the modified Kinyoun, Ziehl-Neelsen, and Fite-Faraco methods• Culture: at 36°C for 3 weeks on SDA -waxy colonies with orange pigmentation while colonies on LJ medium-moist and glaborous. • urease positivity in 12 hours and non utilization of lactose.

• It mimics pulmonary tuberculosis in both clinical symptoms and radiological characteristics.

• chest radiographic manifestations are pleomorphic and non-specific. Consolidations and large irregular nodules, often cavitary, are most common; nodules, masses and interstitial patterns also occur. Upper lobes are more commonly involved

Disseminated disease occurs in about one half of pulmonary nocardiosis cases. CNS is the most common site, others being skin and subcutaneous tissue(Actinomycetoma ,cellulitis), kidney, bone and muscles

• treatment of choice - sulphonamides ( Trimethoprim and Sulphamethoxazole ) associated with surgical drainage when required.

• Minocycline has been recommended for treating patients with nocardiosis who have sulphonamide hypersensitivity.

• Other drugs which may have in vitro activity against Nocardia are Cycloserine, Clindamycin, Ampicillin and Amikacin.

Silicosis- occupational lung disease

• Grinder’s disease• Inhalation of silica particles ( crystalline forms are

most fibrogenic)- engulfed by macrophages- release cytokines for fibroblast proliferation and collagen deposition.

• asso. with increased susceptibility to TB due to CMI• Assymptomatic or present –proggressive dyspnoea,

cough and pleuritic pain• CXR- diffuse miliary or nodular pattern in upper and

mid zones, egg-shell calcification of hilar nodes• CT scan – characteristic “crazy-paving” pattern

Lymph node with rim calcification – ‘’egg shell”

Sarcoidosis

• Sarcoidosis is a multisystem inflammatory disease of unknown etiology that predominantly affects the lungs and intrathoracic hilar (bilateral)lymph nodes.

• presence of noncaseating granulomas in affected organ tissues and shows characteristic inclusions

-Schaumann bodies:- laminated, calcified, proteinaceous concretions-Asteroid bodies :-stellate inclusions within giant cells

1)Pulmonary Involvement-dyspnea, dry cough, vague chest discomfort and wheezing.• Chest radiographs in patients with sarcoidosis have been

classified into four stages: • stage 1, bilateral hilar lymphadenopathy without infiltration.• stage 2, bilateral hilar lymphadenopathy with infiltration.• stage 3, infiltration alone. • stage 4, fibrotic bands, bullae, hilar retraction, bronchiectasis,

and diaphragmatic tenting.

• Skin:a)Erythema nodosumb)Lupus perrnio: purple blue shiny swollen lesions on nose,cheeks,lips,ears

• Eye:Blurred vision, pain, photophobia and dry eyesChronic uveitis leads to glaucoma, cataracts and blindness, Keratoconjunctivitis sicca,Papilledema• Mikulicz syndrome:- eyes n concurrent salivary

gland involvement• Bone marrow: phalangeal predilection‘punched out’ lytic lesions

• Löfgren's syndrome- acute condition triad of-Arthralgia.-erythema nodosum-bilateral hilar adenopathy

• Heerfordt-Waldenstorm's syndrome : (uveoparotid fever)

-Anterior Uveitis-B/L Parotid enlargment-Facial nerve palsy

• Liver- hepatomegaly or biochemical evidence of disease Cholestasis, fibrosis, cirrhosis, portal hypertension, and the Budd-Chiari syndrome have been seen

• Spleen- gross spleenomegaly• Heart -Conduction abnormalities,Cardiomyopathy

Intractable arrythmias,sudden death • CNS-cranial nerve involvement, basilar meningitis,

myelopathy,optic neuritis,Peripheral neuropathy• Renal-Granulomatous interstitial nephritis

produces renal failure,Kidney stones secondary to hypercalcemia and hypercalciuria

Diagnosis

1)Blood-Lymphocytopenia,Mild eosinphilia, Increased E.S.R, Hyperglobulenemia, raised angiotensin converting enzyme, raised calcium(serum & urine)2)Bronchiole alveolar lavage shows increased lymphocytes, CD4/CD8>3.5 in BAL highly s/o3)Tuberculin skin test –negative4)Kveim test:injecting standardized preparation of sarcoid tissue material into the skin-Unique lump formed5)Tissue biopsy- NCGs

Gallium scan :if increase activity seen in • parotid and lacrimal glands- PANDA sign• Right paratracheal and left hilar area- LAMBDA

sign

Treatment: majority recover spontaneosly.Acute sarcoidosis:- NSAIDS, hydroxychloroquine, immunosuppresants, infliximab, thalidomide,Corticosteroid therapy- indications are a.Parenchymal lung diseaseb.Uveitisc.Neurological or cardiac involvementd.hypercalcemia

Wegener Granulomatosis

• Small vessel vasculitis • also k/a Granulomatous Polyangitis• Characteristic triad-1) URT- nose , ear, throat n mouth2) LRT-lungs3) kidney

Clinical Presentation

• Persistent Rhinorrhea• Purulent Nasal Discharge • Sinus Pain• Hoarseness• Stridor• Earache• Nasal Deformity• Proptosis • Cough• Dyspnea• Hemoptysis• Fever (23% at onset)• Weight Loss (15% at onset)• Anorexia• Malaise

• Laboratory Findings:• Leukocytosis• Thrombocytosis as an APR• Normochromic/Normocytic Anemia• Elevated ESR (Correlates with disease activity in 80% of pts)• Normal Complement Levels• Hypergammaglobulinemia (IgA class),• Mildly elevated rheumatoid factor• Positive antiproteinase-3 ANCA (c-ANCA).• Biopsy-Necrotizing granulomatous vasculitis• Urine- hematuria, proteinuria, RBC cast

• CXR: Can have varying presentation.Nodules,Cavitary lesions,Alveolar opacity,Interstitial changes,Pleural opacitiesTreatment:- pulse cyclophosphamide + steroids

Crohn’s disease

• Is a form of inflammatory bowel disease• m/c site- terminal ileum (regional enteritis), rectum

spared• Skip lesions--- cobblestone app• Clinically, radiologically and histopathologically mimic TB• Lesions- ulcerative, hypertrophic or both• Diagnosis- endoscopy & Biopsy, ASCA antibodies• Treatment- corticosteroids, immunosuppressants and

biologic agents. All this flare up TB infection

Malignancies

• ovarian cancer- esp of epithelial variant mimics- ascites, b/l tubo-ovarian masses, raised peritoneal fluid ADA and serum Ca-125 Laparotomy- tubercles• Other- sq. cell ca of oral cavity, small cell ca

lung, lymphomas• Histopathology and immunohistochemical

staining