The course of multidrug-resistant pulmonary tuberculosis in HIV-infected people with COVID-19

Aim. To analyze the course of multidrug-resistant tuberculosis (MDR-TB) in HIV-infected people, depending on the time to COVID-19 diagnosis, using the example of clinical cases from our own observation. Materials and methods. The article presents 3 clinical cases of our own observation of MDR-TB in HIV-infected on the time to COVID-19 diagnosis in patients, non-profit enterprise Regional Results. In clinical case 1, in an HIV-infected patient, MDR TB was detected after COVID-19. This clinical case has shown that after mild and treated COVID-19, even on the background of severe immunosuppression, but with AMBT and ART timely prescribed, MDR-TB in the patient had a favorable course with positive dynamics. In clinical case 2, in an HIV-infected patient, MDR-TB was detected concomitantly with COVID-19. The clinical case indicated that the patient received all 3 therapies for MDR-TB, HIV and COVID-19 in full and on time. In contrast to clinical case 1, the patient was diagnosed with a more severe process that required a longer period of treatment, although it was effective. In clinical case 3, an HIV-infected patient with COVID-19 was diagnosed after 5 months of MDR-TB treatment. Against this background, there was culture positivity. But after prescription of appropriate COVID-19 treatment against the background of AMBT and ART, positive dynamics and culture negativity were determined. All 3 patients completed antimycobacterial therapy of MDR-TB with results – recovery. Conclusions. Regardless of the HIV infection duration with underlying severe immunosuppression (<200 CD4 lymphocyte cells) and the time to COVID-19 diagnosis (before, during or after the diagnosis of MDR-TB) on the background of timely therapy of MDR-TB, HIV and COVID-19, positive results can be achieved while saving the lives of patients. 4 tuberculosis). HIV infection, IV clinical stage. Oropharyngeal candidiasis. Laryngeal neoplasms.

tuberculosis co-infection are more likely to have severe disease and death compared to patients with COVID-19 alone [9].
However, Ş. Gül et al. [7] in their study did not observe an effect of the simultaneous course of tuberculosis and COVID-19 on morbidity or mortality. But the authors pointed out that patients with early tuberculosis (TB) disease in areas with a high Mycobacteria circulation might be at a greater risk of contracting COVID-19.
Data from a meta-analysis by Y. Gao et al. [5] showed that TB is associated with an increased risk of severe COVID-19, because when patients suffer from previous respiratory disease, resistance to viruses is low and they tend to develop acute respiratory distress syndrome.
Crisan-Dabija R. et al. [12] suggest, that the synergism of COVID-19 virus and TB, by interfering with the immune responses of the human body, contributes to more severe clinical evolution.
Therefore, TB may be a risk factor for the progression of COVID-19 with the development of severe complications, and COVID-19 contributes to the progression of TB [5].
Furthermore, COVID-19 occurs regardless of the occurrence of TB (before, during, or after the diagnosis of active TB), and TB is associated with an increased risk of mortality in patients with COVID-19 [11].
The risk factors for COVID-19 and TB are concomitant diseases, among them HIV infection [11]. The COVID-19 pandemic is a serious threat to people, living with HIV/ AIDS. The risk of death from COVID-19 among people living with HIV/AIDS is 2 times higher than in the general population.
In countries with a high TB/HIV co-infection burden, where Ukraine is included, the COVID-19 pandemic is of justifiable concern, because these three diseases closely interact with each other.
In the literature, we have found only one article focused on the study of the simultaneous course of Multidrugre sistant TB (MDR-TB)/HIV/COVID-19. For example, J. L. Tamuzi et al. [10] in their study indicated TB as a risk factor for COVID-19 (severity and mortality) regardless of HIV status.
Thus, the features of the MDR-TB course in HIV-infected people with COVID-19 remain deficiently examined in the literature and is a topical issue today.

Aim
To analyze the course of MDR-TB in HIV-infected people depending on the time to COVID-19 diagnosis using the example of clinical cases from our own observation.

Materials and methods
The article presents 3 clinical cases of our own observation of MDR-TB in HIV-infected persons depending on the time to COVID-19 diagnosis in patients, who were treated at the Pulmonary Tuberculosis Department No. 2, clinical base of the Department of Tuberculosis and Pulmonology ZSMU -Municipal non-profit enterprise "Zaporizhzhia Regional Phthisiopulmonology Clinical Medical and Diagnostic Center" of Zaporizhzhia Regional Council (MNPE "ZRPCMDC" ZRC).

Results
Clinical case 1. Patient K., 39 years old. From the anamnesis: HIV infection was detected on 07.2019. Antiretroviral therapy (ART) was started on 08.2019.
In August 2020, a result of polymerase chain reaction (PCR) was positive, after contact with a man, who was diagnosed with COVID-19.
The course of COVID-19 on the background of HIV infection was mild (loss of smell, weakness, low-grade fever, mild cough), chest X-ray changes were not detected. COVID-19 treatment in combination with ART was effective and the control PCR result was negative. However, low -grade fever persisted in the patient. She had no past history of TB.
According on the comparison plain X-ray + lateral X-ray from 10.2020 (Fig. 1), the following changes were found: in the apical segment of the left lower lung lobe, there were numerous peribronchial foci, which merged into infiltrates up to 15 mm of homogeneous structure; other pulmonary fields without changes; structural roots; sinuses were free.
The patient was referred to MNPE "ZRPCMDC" ZRC for further examination.
Fibrobronchoscopy (FBS) revealed ulcerative tuberculosis B6, which was detected on the left with grade II stenosis. Mycobacterium tuberculosis (MBT) strain resistant to rifampicin (R) was isolated in bronchoalveolar lavage (BAL) by molecular genetic method (MG).
Abdominal ultrasound: echo-signs of moderate diffuse changes of the liver, gallbladder deformation, chronic cholecystitis, diffuse pancreatic changes.
According the obtained data, the diagnosis was established: rifampicin-resistant tuberculosis (Rif TB) The patient was hospitalized to the Pulmonary Tuberculosis Department No. 2 of MNPE "ZRPCMDC" ZRC, where she was prescribed a course of antimycobacterial therapy (AMBT) according to the scheme for category 4. After 3 weeks, we obtained results of the BAL liquid culture showing resistance to isoniazid (H) and streptomycin (S). The diagnosis Rif TB was changed to multidrug-resistant TB (MDR-TB), culture (C) +, resistance 1 (HRS). The TB treatment regimen was not adjusted based on the drug susceptibility test (DST) data, because the HS resistance detected had no effect on the AMBT regimen previously prescribed.
After one month of AMBT, according the data of the FBS from 11.2020, positive changes were diagnosed seen in resorption of B6 ulcerous TB on the left side; the previously detected stenosis was not diagnosed. At the same time, MBT was not isolated from the BAL and sputum.
After 3 weeks of AMBT (01.2021), a control chest X-ray examination ( Taking into account the positive radiological dynamics, cultural negativity after 1 month since AMBT, the patient was discharged from the hospital for outpatient treatment. In April 2020, the patient complained of taste and smell loss, weakness, fever up to 38 °C, cough and scarce    sputum, chest pain and shortness of breath during exercise. Firstly, a PCR was performed, as the patient had contact with COVID-19 patient whose result was positive. A family physician prescribed an appropriate treatment for 10 days, at the end of which, PCR test result was negative for COVID-19. The general condition did not improve. Chest X-ray from 04.2020 (Fig. 4) revealed the follow-ing changes: a massive area of infiltration in S1 + 2 on the left connected with the infiltrated root of the lung; destruction up to 2.0 cm in diameter seen in the infiltration zone.
The patient was referred to MNPE "ZRPCMDC" ZRC for further examination, after being detected with the X-ray changes.
According the data obtained, the diagnosis was estab- The patient was hospitalized to the Pulmonary Tuberculosis Department No. 2 MNPE "ZRPCMDC" ZRC, where she was prescribed a course of AMBT according to the scheme for category 4. We obtained results of the liquid sputum culture showing resistance to isoniazid (H), rifampicin (R), pyrazinamide (Z), ethambutol (E). The diagnosis Rif TB was changed to MDR-TB, C +, resistance 1 (HRZE). The TB treatment regimen was not adjusted based on the DST data, because the HRZE resistance detected had no effect on the AMBT regimen previously prescribed.
After 2 months of AMBT (06.2020), the patient was sputum culture positive despite the negative radiological dynamics.
Plain chest X-ray + CT of the left upper lung lobe 9.0 (Fig. 5A, 5B): in S1 + 2 of the left lung, the massive area of infiltration was connected with the infiltrated root of the lung; a destruction up to 2.5 cm was seen in the zone of infiltration; in the left lower lung lobe and in the right lung -numerous foci of dissemination; sinuses were free.
After 4 months of AMBT (08.2020), there was sputum culture-negative conversion, and the radiological dynamics was positive.
Plain chest X-ray + CT of the left upper lung lobe 9.0 (Fig. 6A, 6B): in the left upper lung lobe, the focal infiltration was partially resorbed, destruction was not defined; in the right lung, the foci of dissemination were partially resorbed.
The patient, on his own initiative, underwent chest CT in 08.2020 (Fig. 7): left-sided plural effusion of 106 × 28 mm and pleural miliary foci of 3-2 mm were defined. Multiple compacted foci from 2-3 mm to 10-13 mm in diameter were defined in C1/2, C3, C6 of the left lung. An infiltrate of 75 × 30 mm in size with lumens of deformed bronchi was seen in C3 of the left lung and paramediastinal lobe. Areas of "frosted glass" were not detected.
After 6 months of AMBT (10.2020), the patient was sputum culture negative, but the radiological dynamics became worse.
Plain chest X-ray + CT of the left upper lung lobe 9.0 (Fig. 8А, 8B): the increased in size infiltration area in the left upper lung lobe extending to the root of the lung was seen; bronchial lumens were traced against the background of infiltration, destruction was not defined; in the left lower lung lobe and in the right lung, numerous focal shadows of medium intensity were revealed against the background of a deformed lung pattern; the structure of the left root was reduced, the right root -without changes.
The patient was diagnosed with worsened asphyxia, so a control spirography was performed: degree II respiratory insufficiency.
Clinical case 3. Patient K., 52 years old. From the anamnesis: HIV infection was first detected in 2015 during the treatment of NDTB. He refused ART. Anti-TB treatment was effective and the patient recovered.
In August 2020, the patient complained of throat irritation, hoarseness of voice, discomfort when swallowing, and foreign body sensation in his throat. The patient went to an otorhinolaryngologist, who prescribed him an examination.
Thus, the laryngeal tomography of 12.0-12.5 (Fig. 9A,  9B) showed asymmetry of the aryepiglottic fold on the right side due to an additional mass in it. Pyriform sinuses were not changed. Supraglottic and subglottic spaces -without changes. Conclusion: neoplasm of the right cranial -epiglottis fold.
The patient categorically refused to be consulted by the oncologist.
On the tomography of the upper lung lobes 7.0-9.0 (Fig. 10), the following changes were found: merging infiltrations with destructions up to 1.0 cm in diameter in the upper lung lobes (more on the left) and in the left C6.
The patient was referred to MNPE "ZRPCMDC" ZRC for further examination.
The patient was hospitalized to the Pulmonary Tuberculosis Department No. 2 MNPE "ZRPCMDC" ZRC, where he was prescribed a course of AMBT, according to the scheme for category 4, ART and treatment of opportunistic infections (biseptol, fluconazole).
After 2 months of AMBT (11.2020), positive dynamics were determined, manifesting by sputum culture negativity (M -, C -) and partial resorption of infiltrative changes in the lungs. Plain chest X-ray + Tomography of the upper lung lobes 7.0 (Fig. 11A, 11B).
Plain chest X-ray + Tomography of the upper lung lobes 7.0 (Fig. 12A, 12B)): fibro-bullous changes, polymorphic foci and infiltrates with destructions up to 1.0 cm in diameter were identified on the right upper lobe and C6 on the background of mixed fibrosis.
In the left upper lobe, pneumatosis was reduced, interlobar pleura was compacted at the level of the posterior third rib. In the middle pulmonary field, polyfibrosis, localized polymorphic foci and infiltrates with destructions from 0.5 cm to 2.0 cm in diameter were seen with a wide extension to the root. The root was deformed, fibrously modified, pulled up to the upper. Pulmonary heart.
GBA The additional COVID-19 treatment was prescribed for the patient.
In March 2021 (one month after the diagnosis of COV-ID-19), the patient was sputum culture negative (M-), and blood inflammatory changes were resolved being characteristic of COVID-19.
The patient was discharged from the hospital for outpatient treatment.

Discussion
In clinical case 1, in the HIV-infected patient, MDR-TB was detected after COVID-19 diagnosis. The patient was HIV-positive for a year and received ART since HIV infection was diagnosed. All the time, the patient was determined with severe immunosuppression (<200 CD4-lymphocyte cells). She had no previous history of TB. TB was detected after 2 months following COVID-19, which was effectively treated. The course of COVID-19 was not difficult and without X-ray changes. But after the COVID-19, subfebrile temperature persisted, which became the reason for the X-ray examination, where characteristics of TB changes were found. This clinical case has shown that after mild and treated COVID-19, even on the background of severe immunosuppression, but with timely prescribed AMBT and ART, the MDR-TB course in patient was favorable with positive dynamics.
In clinical case 2, in the HIV-infected patient, MDR-TB was detected concomitantly with COVID-19. The patient was HIV-infected for 15 years and received ART for 10 years since diagnosis of HIV infection. He had no past history of TB. During 4 months of AMBT, the patient had severe hematological changes characteristic of COVID-19, which indicated a significant effect of active COVID-19 process on the background of severe immunosuppression caused by HIV infection (100 CD4 lymphocyte cells). These changes might have inhibited the rapid achievement of positive results in the treatment of MDR-TB. At the same time, after 6 months, respiratory insufficiency worsened in the patient.
The clinical case has indicated that the patient received all 3 therapies for MDR-TB, HIV and COVID-19 in full and on time. In contrast to clinical case 1, the patient was diagnosed with a more severe process that required a longer period of treatment, although it was effective.
In clinical case 3, the HIV-infected patient with COVID-19 was diagnosed after 5 months of MDR-TB treatment. The patient suffered from HIV infection for 5 years, did not receive ART (refusal). The patient also had severe immunosuppression caused by HIV infection (146 CD4 lymphocyte cells). He started ART only during the treatment of MDR-TB, so 5 years after the diagnosis of HIV infection. The patient had the past history of TB (5 years ago). MDR-TB was detected during examination as a result of laryngeal neoplasm diagnosis. After 2 months of AMBT, the positive dynamics was determined manifesting by sputum culture negativity (M-, C-) and partial resorption of infiltrative changes in the lungs. But after 5 months of AMBT, the patient was diagnosed with COVID-19 with severe clinical symptoms, increasing intoxication and bronchopulmonary syndromes. Alongside this, sputum culture was positive. But after prescription of appropriate COVID-19 treatment against the background of AMBT and ART, positive dynamics and culture negativity were determined.
All 3 patients completed AMBT of MDR-TB with result -recovery.
As we can see, COVID-19 occurred independently of the MDR-TB occurrence (before, during or after the diagnosis of active TB) in HIV-infected patients, confirming the data of D. Visca et al. [11] and disproving the data of Y. Gao et al. [5]. In the HIV-infected patient with recurrent TB (clinical case 3), COVID-19 synergism with MDR-TB contributed to the more severe course and more severe clinical evolution, which complemented the data of J. L. Tamuzi et al. [10] and R. Crisan-Dabija et al. [12].

Conclusions
Regardless of the HIV infection duration with underlying severe immunosuppression (<200 CD4 lymphocyte cells) and the time to COVID-19 diagnosis (before, during or after the diagnosis of MDR-TB) on the background of timely therapy of MDR-TB, HIV and COVID-19, positive results can be achieved while saving the lives of patients.
Prospects for further research. Further study of interesting and relevant clinical cases of MDR-TB course in combination with other diseases in order to determine the prognosis for patients' life and management tactics.