Misdiagnosed pulmonary Tuberculosis Zhanna Laushkina, MD, PhD Novosibirsk TB Research Institute Novosibirsk, Russia

Novosibirsk Tuberculosis Research Institute 2

Supervision zone of NTRI 2/3 territory of Russia near 17% population 3

Novosibirsk TB Research Institute Strong governmental mandate for TB Control Certified to educate in Health Care issues Official feed-back and monitoring Ability to initiate changes in official TB Control regulations, based on scientific analysis and results and approval 4

NTRI Quality control service Clinical departments Scientific department Laboratory service NCE 2015 for WHO SRLN Network NTRI-WHO CC RUS-123 Therapeutic department for drug sensitive TB Scientific and organizing sector Bacteriological laboratory Quality control service Therapeutic department for drug resistance TB laboratory and experimental sector Clinical diagnostic laboratory Surgical department Clinical studies Molecular Genetic laboratory Extra pulmonary TB department Diagnostic departments

Areas of research activity Epidemiological TB monitoring in Siberian and Far East Federal Districts Development of new approaches and TB management mechanisms in Siberian and Far East Federal Districts Diagnostic and treatment methods improvement Differential diagnosis of pulmonary tuberculosis Improvement of surgical treatment for patients with pulmonary and extrapulmonary TB

The proportion of patients from supervised regions and Novosibirsk region in 2016 (%)

Complex anti-TB therapy for patients with TB (1) Inhalation with anti-TB drugs, bronchodilators, mucolytics Physiotherapy

Complex anti-TB therapy for patients with TB (2) Treatment of comorbidities Early rehabilitation (anti-stress neurophysiological correction)

Complex anti-TB therapy for patients with TB (3) Sanatorium treatment

TB incidence (per 100 000 of population)

Purpose of the study To analyze causes of diagnostic errors and improve the quality of in-hospital management for patients supposed to have pulmonary TB

Research object Medical records of 230 most difficult diagnostic cases Previously established diagnosis of pulmonary TB was rejected Noncomparative retrospective study OR and 95% CI were presented 13 13

Clinical and laboratory Methods Clinical and laboratory analysis Analysis of medical history Physical examination Laboratory methods Instrumental methods of Endoscopy X-ray CBC, urinalysis, blood chemistry, Microscopy, Culture, etc. Respiratory function Biopsy 14 14

Structure of clinical cases Misdiagnosed pulmonary TB n = 230 Communitн-acquired pneumonia Lung cancer (24 %) Sarcoidosis (15 %) COPD (5 %) (46 %) Other diseases (10 %)

Comorbidity and bad habits COPD 13 % Gastrointestinal diseases – 24 % Cardiovascular diseases – 14 % Viral hepatitis B or C – 8 % Diabetes – 3 % Other diseases – 19 % Alcohol addiction – 7 % Drug addiction – 3 % Smoking – 60 %

Lung cancer (1) Males 65 %, average age 55 ± 14 yrs. The period between the disease manifestation and correct hospital diagnosis was 106±68 days, between first symptoms and seeking medical care - 25±30 days. 39% of patients were previously treated against assumed pneumonia before to the TB hospital. All patients admitted to the hospital with wrong diagnosis "pulmonary TB", a principal cause was misinterpretation of chest X-ray results. 48% of patients have been receiving anti-TB treatment before a correct diagnosis was made.

Lung cancer (2) Negative association with diagnosis of lung cancer : acute disease beginning, fever, absence of hematological changes, growth of nonspecific microflora in sputum. Positive association with diagnosis lung cancer: age old, low body weight, lost of appetite, dyspnea, leukocytosis, ESR acceleration, lymphopenia, rounded opacities on chest X-ray, pleural effusion, presence of atypical cells in sputum,

Clinical case (1) Patient B, 46 years old, unemployed Complaints: cough, dyspnea, weakness, loss of appetite, chest pain, weight loss 3 weeks of anti-TB treatment before admission to the NTRI At admission to NTRI: In CBC leukocytosis, lymphopenia, accelerated ESR, thrombocytosis anemia AFB in sputum not detected Chest X-ray widespread, bilateral lesion of lung tissue Atypical cells in sputum After endoscopy: Cancer of stomach

Chest X-ray (widespread-metastatic cancer)

Community-acquired pneumonia (1) Males 62%, average age was 47 ± 17 yrs. Absence of laboratory inflammatory hematological disturbances - 29% of cases. Absence of auscultative lungs changes - 61% of patients. Process was localized in I and/or II segments - 77%, in VI segment - 13%. Destructive cavities on chest X-ray – 19% of cases. Only from 31% of patients growth of nonspecific microflora in sputum was identified In 7% of all cases a few acid-fast bacilli were found in sputum by luminescent microscopy (that we suppose as false-positive result).

Community-acquired pneumonia (2) Negative association with diagnosis pneumonia Positive association with diagnosis pneumonia Absence of symptoms (OR 0.31, 95% CI 0.18-0.51), Absence of auscultative lungs changes (0.53, 95% CI 0.33- 0.85), Low body weight (OR 0.54, 95% CI 0.29-0.99), Destructive cavities on chest X-ray (OR 0.38, 95% CI 0.22— 0.66), Detection of AFB (OR 0.22, 95% CI 0.10-0.49). Male sex (OR 1.63, 95% CI 1.01-2.65) Alcoholism (OR 2.63, 95% CI 1.09-2.79) Acute disease beginning (OR 4.46, 95% CI 2.16-5.54) Fever (OR 2.84, 95% CI 1.76- 4.61) Cough (OR 1.74, 95% CI 1.09-2.79) Limited changes on chest X- ray (OR 2.17, 95% CI 1.33- 3.54) Growth of nonspecific microflora in sputum (OR 3.24, 95% CI 1.87-5.63)

Sarcoidosis (1) Males 37 %, average age was 44.6 ± 11.8 yrs. The period between the disease manifestation and correct final diagnosis was 167.7±131.9 (mean±SD) days. 26 % of patients were previously treated against assumed pneumonia before admittion to the TB hospital. 54 % of patients have been receiving anti-TB treatment before a correct diagnosis was made (120.7±99.4 days). All patients have been hospitalized with wrong diagnosis “pulmonary TB”. In 6 % of all cases a few acid-fast bacilli were found in sputum by luminescent microscopy.

Sarcoidosis (2) Urban residents (OR 2.58, 95% CI 1.04-6.38), Positive association with diagnosis sarcoidosis: Urban residents (OR 2.58, 95% CI 1.04-6.38), Office workers (OR 4.24, 95% CI 2.07-8.68), No complaints (OR 3.42, 95% CI 1.64-7.16), Normal parameters of CBC (OR 2.29, 95% CI 1.14-4.61), Dissemination on chest X-ray (OR 77.63, 95% CI 18.14-332), Enlarged intrathoracic lymph nodes (OR 18.6, 95% CI 3.21-141). нОмал

Sarcoidosis (3) Negative association with diagnosis sarcoidosis: male sex (OR 0.32, 95% CI 0.16-0.66), poorness (OR 0.18, 95% CI 0.06-0.52), acute disease beginning (OR 0.24, 95% CI 0.08- 0.70), low body weight (OR 0.10, 95% CI 0.01-0.73), fever (OR 0.23, 95% CI 0.07-0.78), weakness (OR 0.43, 95% CI 0.21-0.88), productive cough (OR 0.34, 95% CI 0.13-0.91), infiltrative changes on chest X-ray (OR 0.02, 95% CI 0.01-0.12), destructive cavities on chest X-ray (OR 0.05, 95% CI 0.01-0.39), detection of AFB (OR 0.22, 95% CI 0.05-0.96).

Clinical case (2) Patient D, 30 years old, cook Complaints: did not have Patient D, 30 years old, cook MTB + (by fluorescence microscopy) before admission to the NTRI 2 months anti-TB treatment before admission to the NTRI On admission to NTRI: In CBC: normal levels AFB in sputum not detected CT scan: Widespread bilateral lesion in lung tissue, cavities, enlarged lymph nodes of the bifurcation group for 3 months received anti-TB treatment VATS biopsy: sarcoidosis Without effect

CT scan on admission

Biopsy result Sarcoid type granulomas surrounded by mature fibrosis in the lung tissue Sarcoid granulomas and mature fibrosis in the lymph node

COPD Negative association with diagnosis COPD: Males 83.3 %, average age was 54,1 ± 10,8 yrs. Negative association with diagnosis COPD: Age less than 30 years (OR 0.13, 95% CI 0.03-0.51) Villagers (OR 0.11, 95% CI 0.02-0.51) Positive association with diagnosis COPD: Age over 45 years old (OR 5.78, 95% CI 1.25-26.76) Smoking (OR 1.74, 95% CI 1.09-2.79) Cough (OR 16.9, 95% CI 2.17-82.64) Dyspnea (OR 4.98, 95% CI 1.56-15.96) Growth of nonspecific microflora in sputum (OR 3.24, 95% CI 1.87-5.63) Wheezing with auscultation (OR 10.4, 95% CI 1.91-56.5) Pneumosclerosis on chest X-ray (OR 8.78, 95% CI 2.43- 31.62) Normal X-ray (OR 25.79, 95% CI 6.97-95.41)

On admission to NTRI: Liquid culture (Вастес 960) - M. fortuitum; GeneXpert + R resistance. In CBC: normal levels. Spirography- the vital capacity of the lungs is significantly reduced, marked by a sharp violation of bronchial patency. The ventilation capacity of the lungs is sharply reduced. Clinical case (3) Patient B, 39 years old, Unemployed. In 2013 COPD was diagnosed. Pulmonary tuberculosis was diagnosed in 2013 in prison. Antituberculous treatment until 2015. In September 2016 AFB were found in sputum by luminescent microscopy. In culture was growth of M. fortuitum. Patient was sent to NTRI. The patient had a combination of pulmonary tuberculosis, mycobacteriosis and COPD.

CT scan on admission

CT scan after 2 months

M. fortuitum in the smear, by Ziehl-Nielsen mycroscopy

Growth of M. fortuitum colonies on the Levenstein-Jensen medium

Predictors misdiagnosis of tuberculosis Socio-demographic predictors Predictors misdiagnosis of tuberculosis Clinical predictors Laboratory predictors Radiological predictors

Factors found to be associated with false-positive TB diagnosis in all patients detection of AFB in sputum (OR 55.7, 95% CI 7.0-444) destructive cavities on chest X-ray (OR 0.38, 95% CI 0.22—0.66) nonspecific inflammatory findings detected by flexible bronchoscopy (OR 2.7, 95% CI 1.0-7.2), low body weight (OR 9.4, 95% CI 3.5- 25.4) age more than 40 years (OR 1.8, 95% CI (1.1-2.7)).

Conclusion Several reasons for misdiagnosis of tuberculosis were found, but the main reason was misinterpretation of chest X-ray. It is important to consider low sensitivity of chest X-ray. Other important reasons for misdiagnosis: non-typical symptoms, false-positive detection of AFB in sputum, comorbidity, similarity of clinical and radiological symptoms for some of lung diseases. Often diagnosis requires histological confirmation. Due to high incidence of tuberculosis in our country there is a tendency to over diagnose of tuberculosis. The results would allow to optimize the diagnostic approaches to such patients.

Thank you!