Mycobacterium tuberculosis (MTB) continues to be the commonest opportunistic infection amongst people living with HIV (PLHIV) worldwide . According to the WHO Global Tuberculosis (TB) report, in India at the end of 2018 the rate per 100 000 population for all TB and HIV-positive TB was estimated to be 199 and 6.8, respectively .
Coronavirus disease 2019 (COVID19) is emerging as a major public health problem in low-income and middle-income countries that already have high burden of HIV infection and TB . As of 22 July 2020, approximately 1.2 million individuals were diagnosed with severe acute respiratory syndrome-coronavirus-2 (SARS-COV-2) infection in India with approximately 400 000 active cases .
Clinical and radiological features of pulmonary TB (PTB) and COVID19 may overlap in these settings as presentations of PTB can be atypical in advanced HIV disease. We report an individual with advanced HIV disease who presented with features of COVID19 but was diagnosed to have PTB.
On 25 May 2020, a 57-year-old gentleman with well controlled hypertension presented to us with fever (101 °F) and dry cough of 8 days duration. He did not complain of breathlessness, sore throat, myalgia and anosmia/ageusia. He resided in an area designated as a COVID19 hot spot. On examination he was obese (BMI 34.2 kg/m2), had fever (101 °F) and a respiratory rate of 20/min. His oxygen saturation (SpO2) was 97% on room air. His laboratory evaluation revealed anemia (due to bleeding hemorrhoids), normal white blood cell count with lymphopenia [absolute lymphocyte count (ALC) = 561/μl] and normal platelet count. His erythrocyte sedimentation rate (ESR) was 79 mm/h. Liver enzymes revealed aspartate aminotransferase (AST) = 92 U/l and alanine transaminase (ALT) = 81 U/l. Inflammatory markers revealed an elevated high-sensitivity C-reactive protein (hsCRP) = 13.3 mg/dl, ferritin = 791.61 ng/ml and d-dimer = 6014.85 ng/ml. His chest radiograph was unremarkable. Prior to presentation, his throat/nasal swab (T/NS) was negative for SARS-COV-2 by reverse transcriptase PCR (RT-PCR).
He was diagnosed with HIV-1 infection in March 2020 with a CD4+ cell count of 19/μl Tenofovir alafenamide/emtirictabine (FTC)/dolutegravir (DTG) along with trimethoprim-sulphamethoxazole (TMP-SMX) was initiated. However, he discontinued treatment after a month due to inability to access treatment during the lockdown period. He was initiated on tenofovir disoproxil fumarate (TDF)/lamivudine/efavirenz along with TMP-SMX at a local clinic 3 days prior to presentation. He had no past history of TB and was not coinfected with hepatitis B and/or hepatitis C virus.
Considering high likelihood of COVID19, a chest computed tomography (CT) was performed that revealed bilateral ground glass opacities (GGO) with air space consolidation predominantly involving lower lobes (Fig. 1) suggestive of viral pneumonia. There was no evidence of miliary nodules, mediastinal adenopathy or tree-in-bud branching nodules to suggest endobronchial spread of infection. Broncho-alveolar lavage was negative for SARS-COV-2 (RT-PCR), Pneumocystis jiroveci (silver methenamine), but acid-fast bacilli (AFB) were seen. A multiplex PCR to rule out other infections and TB culture was not performed. GeneXpert MTB Ultra (Cepheid Inc., Sunnyvale, California, USA) was positive for MTB complex (medium) and rifampicin resistance was not detected. Trans-bronchial lung biopsy revealed focal epithelioid histiocytic granulomas with central necrosis and several AFB (Fig. 2a and b).
He initially received parenteral methylprednisolone (40 mg qd) for 2 days which was switched to oral prednisolone (1 mg/kg per day) when four-drug antitubercular treatment (isoniazid, rifampin, pyrazinamide and ethambutol) was initiated. Antiretroviral therapy (ART) was switched to TDF/FTC and DTG (twice a day). Two days later his fever resolved, and he maintained SpO2 at least 94% throughout hospitalization. The hsCRP declined to 2.03 mg/dl with stable ferritin = 885.68 ng/ml. He was discharged 8th day of admission. His clinical status was unremarkable at 1-month post discharge with hsCRP = 6.7 mg/dl, ferritin = 40 ng/ml, d-dimer = 709 ng/ml and ALC = 2200/μl.
In this individual with advanced HIV disease, PTB mimicked the clinical, radiological and hyperinflammatory features of COVID19. The clinical presentation of this individual can be categorized as severe acute respiratory illness (SARI) defined as history of fever or measured fever at least 38 °C, and cough with onset within the last 10 days and requiring hospitalization . This definition was developed for influenza surveillance, however screening for SARS-COV-2 infection amongst all SARI patients has been recommended in India since March 2020 . Prior to the COVID19 pandemic, a study from Brazil documented high prevalence of MTB second only to respiratory viruses amongst profoundly immunosuppressed PLHIV presenting with SARI . The authors of this study underline the importance of pursuing a diagnosis of PTB amongst PLHIV regardless of symptom duration in high TB prevalence settings.
The clinical spectrum of PTB in PLHIV varies according to the degree of immunosuppression. For PLHIV without significant immunodeficiency, TB manifests in the same way as it does in HIV-uninfected individuals. However with advanced HIV disease, cavitary disease is uncommon and disseminated disease with extrapulmonary forms predominate and miliary TB with severe sepsis has occasionally been documented . Case reports also describe PTB presenting with Acute Respiratory Distress Syndrome amongst PLHIV with advanced immunosuppression and also as immune reconstitution inflammatory syndrome (IRIS) [9,10].
In a retrospective study from a tertiary referral center in India, the prevalence of COVID19 amongst individuals presenting with SARI was 39 with 70% having at least one comorbidity . Hence, we have been screening all individuals with SARI for SARS-COV-2 infection including a repeat specimen preferably obtained from the lower respiratory tract amongst those with a negative screening T/NS. In this individual with clinical presentation mimicking COVID19, SARS-COV-2 was negative in both upper and lower respiratory specimens. Coinfection with SARS-COV-2 is very unlikely in this patient as testing was performed on broncho-alveolar lavage, that has been reported to have highest sensitivity as compared with other specimens .
Chest CT has high sensitivity for diagnosis of COVID19 with pooled probability of 84 and 75% for bilateral involvement and GGO, respectively . However, GGO on CT has been described in miliary TB, although this is accompanied by presence of miliary nodules, interlobular septal thickening and necrotic lymph nodes [14,15]. Amongst opportunistic infections in HIV, GGO is more commonly seen with cytomegalovirus pneumonia, lymphocytic interstitial pneumonia and considered virtually diagnostic of pneumocystis jeroveci pneumonia in most cases . In our patient staining for pneumocystis was negative (PCR was not performed) and none of the characteristic radiologic changes associated with TB were present on CT chest.
In a meta-analysis, inflammatory markers like CRP, IL-6 and ESR positively correlated with severity of COVID19 while the association of ferritin was not conclusive . Significantly, advanced immune-suppression in HIV has been associated with high levels of hsCRP, d-dimer and IL-6 along with other inflammatory biomarkers that may not normalize after initiation of ART [18,19]. Moreover, CRP is reported to perform well as a TB screening test for PLHIV with lower CD4+ cell counts [20,21]. Lymphopenia (ALC ≤ 1200/μl) is common amongst patients with COVID19 especially in those with severe disease . Lymphopenia is characteristic of advanced HIV disease and associated with worse prognosis amongst patients initiating ART . Rise in inflammatory markers and lymphopenia in our patient may be attributed to advanced HIV disease and TB coinfection.
This individual responded to antitubercular treatment and steroids. Steroids was used to reduce risk of development of paradoxical TB IRIS . Inflammatory markers and lymphopenia improved at 1 month as compared with baseline values.
Numerous challenges in provision of HIV care has emerged during the COVID19 pandemic. Disruptions in HIV and TB care delivery due to COVID19 containment (e.g. lockdown) and mitigation strategies, management of COVID19 patients overwhelming healthcare systems and disruption in supply chain of antiretrovirals/antitubercular drugs could increase HIV and TB-related deaths by 10 and 20%, respectively, over the next 5 years in high burden countries .
Most of these deaths amongst PLHIV could be attributable to development of opportunistic infections as a consequence of discontinuing antiretroviral drugs. Diagnosis of respiratory opportunistic infections may be missed or delayed when these patients present to care with SARI during the COVID19 pandemic.
In conclusion, this case highlights the importance of considering PTB in the differential diagnosis amongst PLHIV with advanced immune suppression presenting with COVID19 like illness. Simultaneous evaluation for TB should be performed amongst these individuals especially in areas with high burden of TB to rule in either mono-PTB or rule out MTB coinfection with COVID19.
The authors are grateful to the patient for providing consent for publication. We would like to acknowledge staff at Indian Council of Medical Research-National Institute of Virology for performing SARS-COV-2 RT-PCR.
Authors’ contibution: S.P. drafted the article; S.P., P.G., S.G. and C.D. were involved in clinical management of the patient and provided inputs on the article, D.P. performed the microbiology test and reported the histo-pathology, and D.S. and A.A. reported the CT scan.
No funding support received for this work.
Conflicts of interest
There are no conflicts of interest.
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