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CT imaging of HIV-associated pulmonary disorders in COVID-19 pandemic

  • Liya R. Abuladze
    Correspondence
    Corresponding author at: Research and Practical Clinical Center for Diagnostics and Telemedicine Technologies of the Moscow Health Care Department, 127051 Moscow, 24, Petrovka str. 1, Russian Federation.
    Affiliations
    Research and Practical Clinical Center for Diagnostics and Telemedicine Technologies of the Moscow Health Care Department, 127051 Moscow, 24, Petrovka str. 1, Russian Federation

    The Vishnevsky Nаtionаl Mediсаl Reseаrсh Сenter of Surgery, 117997 Mosсow, Bol. Serpukhovskаyа str., 27, Russian Federation
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  • Ivan A. Blokhin
    Affiliations
    Research and Practical Clinical Center for Diagnostics and Telemedicine Technologies of the Moscow Health Care Department, 127051 Moscow, 24, Petrovka str. 1, Russian Federation
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  • Anna P. Gonchar
    Affiliations
    Research and Practical Clinical Center for Diagnostics and Telemedicine Technologies of the Moscow Health Care Department, 127051 Moscow, 24, Petrovka str. 1, Russian Federation
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  • Maria M. Suchilova
    Affiliations
    Research and Practical Clinical Center for Diagnostics and Telemedicine Technologies of the Moscow Health Care Department, 127051 Moscow, 24, Petrovka str. 1, Russian Federation
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  • Anton V. Vladzymyrskyy
    Affiliations
    Research and Practical Clinical Center for Diagnostics and Telemedicine Technologies of the Moscow Health Care Department, 127051 Moscow, 24, Petrovka str. 1, Russian Federation

    I.M. Sechenov First Moscow State Medical University (Sechenov University), 8, Trubetskaya str. 2, 119991 Moscow, Russian Federation
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  • Victor A. Gombolevskiy
    Affiliations
    Artificial Intelligence Research Institute (AIRI), 121170, Kutuzovsky pr. 32, 1, Moscow, Russian Federation
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  • Eleonora A. Balanyuk
    Affiliations
    Clinic of Aesthetic Medicine “Olymp Clinic”, 129090, 7, Sadovaya-Sukharevskaya str.1, Moscow, Russian Federation
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  • Oksana G. Ni
    Affiliations
    City Clinical Hospital №40, Moscow Health Care Department, 8 Sosensky stan, Kommunarka settlement, 129301 Moscow, Russian Federation
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  • Dmitry V. Troshchansky
    Affiliations
    City Clinical Hospital №40, Moscow Health Care Department, 8 Sosensky stan, Kommunarka settlement, 129301 Moscow, Russian Federation
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  • Roman V. Reshetnikov
    Affiliations
    Research and Practical Clinical Center for Diagnostics and Telemedicine Technologies of the Moscow Health Care Department, 127051 Moscow, 24, Petrovka str. 1, Russian Federation
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      Highlights

      • CT DDx in PLHIV is a challenge
      • Five major disease groups with overlapping CT features
      • The review provides radiologists data that may assist the diagnostic decision-making

      Abstract

      Opportunistic infections in people living with human immunodeficiency virus (HIV) are readily detected with thoracic computed tomography (CT), but differential diagnosis remains a challenge. The global COVID-19 pandemic further exacerbates the issue, with SARS-CoV-2 having overlapping CT findings with infections common in HIV patients and complicating prior epidemiological data. We present a pictorial review of CT findings associated with COVID-19-mimicking opportunistic infections that can be encountered in HIV patients. PubMed database was searched for the complete list of relevant conditions, and a Venn diagram was constructed to highlight overlapping entities. The diagram showed five major disease groups: viral pneumonia, fungal pneumonia, bacterial pneumonia, sarcoidosis, and lung cancer. As these pathologies possess a wide range of features, the findings were grouped as “typical” and “other” for easier comprehension with provided relevant epidemiological data and discrepancies observed in available literature. The review highlights the importance of a specific approach to differential diagnosis in immunocompromised patients compared to immunocompetent hosts and the utility of follow-up scans.

      Keywords

      1. Introduction

      The human immunodeficiency virus (HIV) causing acquired immunodeficiency syndrome (AIDS) was simultaneously and independently discovered in 1985 by two groups.
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      The evolution of HIV-1 and the origin of AIDS.
      Initially it was named as lymphadenopathy-associated virus (LAV) by the team of Luc Montagnier
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      Lymphadenopathy associated virus and its etiological role in AIDS.
      and human T-lymphotropic virus type III (HTLV-III) by Robert Gallo et al.
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      • Markham P.
      • Gallo R.
      Human T lymphotropic virus type III infection of human alveolar macrophages.
      Prior to 1996 and the development of effective antiretroviral therapy (ART, or HAART, highly active antiretroviral therapy), AIDS-related disorder was a fatal, mainly because of numerous opportunistic infections (OIs).
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      • Richardson J.T.
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      • Holmberg S.D.
      • Brooks J.T.
      Rates of hospitalizations and associated diagnoses in a large multisite cohort of HIV patients in the United States, 1994–2005.
      The full spectrum of HIV-associated pulmonary infections has been described in several comprehensive reviews.
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      • et al.
      HIV-infected patients with opportunistic pulmonary infections misdiagnosed as lung cancers: the clinicoradiologic features and initial application of CT radiomics.
      The incidence of HIV complications, as well as the life expectancy of people living with HIV (PLHIV), have changed with the advancement in ART and primary prophylaxis usage.
      In 1990s, Pneumocystis pneumonia (PCP) was the most common opportunistic infection in AIDS patients in Europe.
      • Morris A.
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      • Walzer P.D.
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      • Frederick T.
      • et al.
      Current epidemiology of pneumocystis pneumonia.
      After PCP prophylaxis adoption, the incidence of the infection has been decreased.
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      That, and the introduction of HAART, has led to bacterial pneumonia becoming the most frequent type of HIV-associated infections in developed countries.
      • Benito N.
      • Moreno A.
      • Miro J.M.
      • Torres A.
      Pulmonary infections in HIV-infected patients: an update in the 21st century.
      Recently, a novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) was discovered that became a cause of global coronavirus disease 2019 (COVID-19) pandemic. COVID-19 shares computed tomography (CT) findings and clinical manifestations with the infections that are common among PLHIV, closely resembling PCP. It makes differentiation of infection causes difficult even for domain experts. Here we present a pictorial review of typical CT findings associated with COVID-19-mimicking opportunistic infections that can be encountered in AIDS patients.

      2. Materials and methods

      In this review, we used a formal approach to define a list of AIDS-related OIs that share CT findings with COVID-19 in order to minimize potential author bias.
      First, we searched the PubMed database to identify the HIV-associated lung diseases detectable by CT, using the query (“AIDS-Related Opportunistic Infections”[mh] OR AIDS related opportunistic infections OR HIV-Related Opportunistic Infections) AND (“Tomography, X-Ray Computed”[Mesh Terms] OR computed tomography) AND (thorax[mh] OR thorac* OR chest). The relevant conditions are summarized in Supplementary Table A. No exclusion criteria were applied during this and the following step of search.
      The second step was to search the PubMed database to identify diseases with findings similar to COVID-19 CT, using the query (“COVID-19” OR “COVID-19”[MeSH Terms] OR “SARS-CoV-2” OR “sars-cov-2”[MeSH Terms] OR “Severe Acute Respiratory Syndrome Coronavirus 2” OR “NCOV” OR “2019 NCOV” OR “coronavirus”[MeSH Terms] OR “coronavirus” OR “COV”) AND (“Diagnosis, differential”[Mesh] OR mimic* OR differential diagnosis) AND (“tomography, X-ray computed tomography”[Mesh Terms] OR computed tomography. The COVID-19-mimicking conditions are summarized in Supplementary Table B.
      The third step was the building of Venn diagram (Fig. 1) to determine the shared pathological entities between Tables A and B, forming the list of conditions with similar radiographic features that could be observed in HIV-positive patients amid the COVID-19 pandemic.
      Fig. 1
      Fig. 1Venn diagram showing the pulmonary diseases in PLHIV sharing CT findings with CIVID-19-mimicking conditions. Symbol * denotes viral pneumonia with distinctive CT signs. Symbol ** denotes fungal pneumonia with distinctive CT signs.
      The literature selection was performed by screening the abstracts and full texts of the studies. We also performed snowballing to identify articles missed in the search. If several articles with a common research question and similar results were found, the most recent study was included in the review. To minimize the selection bias, each study was independently screened by two reviewers, and the discrepancies were resolved through discussion or after consultations with the third reviewer.
      The representative CT studies with target diseases were selected from the Unified Radiological Information Service (URIS) of the City of Moscow. The use of depersonalized CT studies as illustrative material was approved by the Independent Ethical Committee of the Moscow Regional Office of the Russian Society of Radiologists and Radiographers.

      3. Results

      According to the analyzed published data, the list of conditions with overlapping CT findings between HIV-related pulmonary diseases and COVID-19-mimicking entities consisted of five major disease groups: viral pneumonia, fungal pneumonia, bacterial pneumonia, sarcoidosis, and lung cancer (Fig. 1). Within viral pneumonias, cytomegalovirus pneumonia was singled out as having distinctive CT signs in comparison with other viral infections (Fig. 1). For the same reasons, PCP and invasive aspergillosis were separated from other types of fungal pneumonia (Fig. 1).

      3.1 Viral pneumonia

      HIV-positive patients are at risk of the viral respiratory infections that are frequent among the general population. Before the COVID-19 era, the most common viral infections in patients admitted to the intensive care unit were influenza A virus and rhinovirus.
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      • Yang K.S.
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      Epidemiologic characteristics and clinical significance of respiratory viral infections among adult patients admitted to the intensive care unit.
      COVID-19 pandemic shifted the distribution, with SARS-CoV-2 becoming the most detected respiratory tract pathogen.
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      • Schaaf B.
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      • Pletz M.W.
      • et al.
      The impact of the SARS-CoV-2 pandemic on the prevalence of respiratory tract pathogens in patients with community-acquired pneumonia in Germany.
      In 2020–2021, the decrease in influenza virus incidence reached up to 100% in comparison to pre-pandemic years, depending on the region.
      • Grochowska M.
      • Ambrożej D.
      • Wachnik A.
      • Demkow U.
      • Podsiadły E.
      • Feleszko W.
      The impact of the COVID-19 pandemic lockdown on pediatric Infections—A single-center retrospective study.
      • Olsen S.J.
      • Azziz-Baumgartner E.
      • Budd A.P.
      • Brammer L.
      • Sullivan S.
      • Pineda R.F.
      • et al.
      Decreased influenza activity during the COVID-19 pandemic — United States, Australia, Chile, and South Africa, 2020.
      The following 2021–2022 season has brought the return of influenza, although the incidence was lower than seen before the pandemic.
      • Merced-Morales A.
      • Daly P.
      • Abd Elal A.I.
      • Ajayi N.
      • Annan E.
      • Budd A.
      • et al.
      Influenza activity and composition of the 2022–23 influenza vaccine — United States, 2021–22 season.
      The decline in the flu incidence is not associated with a decrease in testing for influenza, being instead attributed by CDC to COVID-19 mitigation measures, such as lockdown policies, face mask wearing, and increased ventilation of indoor spaces.
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      • Daly P.
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      • Ajayi N.
      • Annan E.
      • Budd A.
      • et al.
      Influenza activity and composition of the 2022–23 influenza vaccine — United States, 2021–22 season.
      There are scarce data on the yearly dynamics of viral infections prevalence other than flu and COVID-19. The current increase of influenza activity indicates a possible activation of other pathogens. The latter include herpes simplex virus, parainfluenza virus, respiratory syncytial virus, and adenovirus. These should be considered in the differential diagnosis when evaluating COVID-19 for HIV patients with respiratory symptoms. It is also important to bear in mind the possibility of cytomegalovirus pneumonia that occurs almost inclusively in immunocompromised patients.
      • Franquet T.
      Respiratory infection in the AIDS and immunocompromised patient.
      With the exception of COVID-19- and cytomegalovirus-associated pneumonia, viral pneumonia radiographic signs do not noticeably distinguish between different infections.
      • Carlicchi E.
      • Gemma P.
      • Poerio A.
      • Caminati A.
      • Vanzulli A.
      • Zompatori M.
      Chest-CT mimics of COVID-19 pneumonia—a review article.
      Typical CT features are nonspecific and include patchy, multifocal or diffuse ground-glass opacities (GGOs) (Fig. 2A-B ), interlobular septal or bronchial wall thickening as well as patchy, multifocal consolidation corresponding to disease course.
      • Duzgun S.A.
      • Durhan G.
      • Demirkazik F.B.
      • Akpinar M.G.
      • Ariyurek O.M.
      COVID-19 pneumonia: the great radiological mimicker.
      Fig. 2
      Fig. 2Typical CT findings associated for different types of viral pneumonia. A, B: axial and coronal views of patchy GGOs (arrows) in 82-years-old woman with viral pneumonia caused by influenza A; C, D: axial and coronal images of GGOs with bilateral and peripheral distribution and interlobular septal thickening (arrows) in 47-years-old man with COVID-19-associated pneumonia; E, F: axial and coronal views of diffuse heterogenous GGOs (white arrows) with focal consolidationmultiple nodules (dark arrows) in 42-years-old man with CMV pneumonia.
      Other CT features include small centrilobular nodules, tree-in-bud opacities and small bilateral pleural effusion.
      • Duzgun S.A.
      • Durhan G.
      • Demirkazik F.B.
      • Akpinar M.G.
      • Ariyurek O.M.
      COVID-19 pneumonia: the great radiological mimicker.

      3.2 COVID-19 pneumonia

      Kerkhoff AD et al. showed that HIV-infected individuals may have an increased risk for severe COVID-19-related outcomes.
      • Kerkhoff A.D.
      • Havlir D.V.
      CROI 2021: Tuberculosis, Opportunistic Infections, and COVID-19 Among People with HIV.
      The risk appears to be driven by older age and comorbidities, mostly hypertension, obesity or hyperlipidemia, chronic obstructive pulmonary disease, and diabetes.
      • Mirzaei H.
      • McFarland W.
      • Karamouzian M.
      • Sharifi H.
      COVID-19 among people living with HIV: a systematic review.
      While the CT features of COVID-19 are non-specific, there are patterns that are typical for the subfamily of coronaviruses.
      • Hanfi S.H.
      • Lalani T.K.
      • Saghir A.
      • McIntosh L.J.
      • Lo H.S.
      • Kotecha H.M.
      COVID-19 and its mimics.
      Typical CT features include bilateral GGOs with apicobasal and peripherial distribution as well as subpleural involvement (Fig. 2C-D).
      Other CT features reflect the disease course and complications: crazy paving sign (GGOs with thickened interlobular septa), coalescent consolidations, subpleural lines and pleural effusions.
      Cytomegalovirus (CMV) is widespread among general population, with prevalence ranging from 45% to 100%, depending on the geographic region.
      • Cannon M.J.
      • Schmid D.S.
      • Hyde T.B.
      Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection.
      CMV pneumonia occurs almost inclusively in immunocompromised patients, including AIDS patients, most commonly following bone marrow and solid organ transplantation.
      • Franquet T.
      Respiratory infection in the AIDS and immunocompromised patient.
      Prior to the introduction of HAART, CMV was associated with high early mortality, being one of the most dangerous OIs for PLHIV.
      • Salomon N.
      • Gomez T.
      • Perlman D.C.
      • Laya L.
      • Eber C.
      • Mildvan D.
      Clinical features and outcome of HIV-related cytomegalovirus pneumonia.
      Currently, there is a controversy considering clinical significance of CMV as a pulmonary pathogen in HIV-positive patients. Some sources claim that the CMV significance is not fully defined,
      • Gianella S.
      • Moser C.
      • Vitomirov A.
      • McKhann A.
      • Layman L.
      • Scott B.
      • et al.
      Presence of asymptomatic cytomegalovirus and epstein-barr virus DNA in blood of persons with HIV starting antiretroviral therapy is associated with non-AIDS clinical events.
      and that CMV pneumonitis is uncommon in patients with HIV.
      • Skalski J.
      • Limper A.
      Fungal, viral, and parasitic pneumonias associated with human immunodeficiency virus.
      On the other hand, Tanaka et al. reported that the CMV coinfection in patients with AIDS in Japan is frequently occurring and has one of the highest mortality rates among the other major AIDS-defining diseases, namely PCP, candidiasis, and active tuberculosis.
      • Tanaka T.
      • Oshima K.
      • Kawano K.
      • Tashiro M.
      • Tanaka A.
      • Fujita A.
      • et al.
      Nationwide surveillance of AIDS-defining illnesses among HIV patients in Japan from 1995 to 2017.
      CMV pneumonia has several CT features distinguishing the disease from other etiologies of viral pneumonia.
      • Carlicchi E.
      • Gemma P.
      • Poerio A.
      • Caminati A.
      • Vanzulli A.
      • Zompatori M.
      Chest-CT mimics of COVID-19 pneumonia—a review article.
      Typical CT features include bilateral basal heterogenous GGOs with subpleural sparing, small centrilobular nodules (Fig. 2E-F).
      Other CT features include halo sign and interlobular septal thickening.
      Unfortunately, the CT findings and clinical features are similar between CMV and adenovirus pneumonia, potentially complicating the final diagnosis.
      • Carrigan Ph.D.D.R.
      Adenovirus infections in immunocompromised patients.

      3.3 Fungal pneumonia

      While invasive fungal infections (IFIs) are an important cause of opportunistic pneumonias in HIV patients, there are scarce and conflicting data on the incidence and mortality rate of IFIs. Some sources claim that 47% of AIDS-related deaths are attributed to IFIs.
      • Denning D.W.
      Minimizing fungal disease deaths will allow the UNAIDS target of reducing annual AIDS deaths below 500 000 by 2020 to be realized.
      Contrary to that, a large prospective cohort study in Japan revealed that the fungal pneumonia mortality in PLHIV was about 4%.
      • Nishijima T.
      • Inaba Y.
      • Kawasaki Y.
      • Tsukada K.
      • Teruya K.
      • Kikuchi Y.
      • et al.
      Mortality and causes of death in people living with HIV in the era of combination antiretroviral therapy compared with the general population in Japan.
      The reported values of IFIs incidence among HIV patients vary widely depending on the country; even within the studies performed in the same geographic area the observed epidemiology can be significantly different.
      • Pfavayi L.T.
      • Denning D.W.
      • Baker S.
      • Sibanda E.N.
      • Mutapi F.
      Determining the burden of fungal infections in Zimbabwe.
      • Marukutira T.
      • Huprikar S.
      • Azie N.
      • Quan S.-P.
      • Meier-Kriesche U.
      • Horn D.
      Clinical characteristics and outcomes in 303 HIV-infected patients with invasive fungal infections: data from the prospective antifungal therapy Alliance registry, a multicenter, observational study.
      • Anwar Khan P.
      Profile of fungal lower respiratory tract infections and CD4 counts in HIV positive patients.
      • Kaur R.
      Fungal opportunistic pneumonias in HIV/AIDS patients: an Indian tertiary care experience.
      The observed inconsistency in reported incidence values may due to uneven distribution of diagnostic tests, resulting in frequent misdiagnosis.
      • Brown G.D.
      • Denning D.W.
      • Gow N.A.R.
      • Levitz S.M.
      • Netea M.G.
      • White T.C.
      Hidden killers: human fungal infections.
      The true burden of IFIs may be significantly underestimated, both in developing and developed world.
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      • Denning D.W.
      • Gow N.A.R.
      • Levitz S.M.
      • Netea M.G.
      • White T.C.
      Hidden killers: human fungal infections.
      According to the review of Sousa-Neto et al., Pneumocystis jirovecii pneumonia (PCP) is the most common IFI among HIV-positive individuals worldwide.
      • de Sousa-Neto A.L.
      • de Brito Röder D.V.D.
      • Pedroso R. dos S.
      Invasive fungal infections in people living with HIV/AIDS.
      Other frequently reported IFIs in HIV patients are cryptococcosis, histoplasmosis, and invasive pulmonary aspergillosis (IPA).
      • Pfavayi L.T.
      • Denning D.W.
      • Baker S.
      • Sibanda E.N.
      • Mutapi F.
      Determining the burden of fungal infections in Zimbabwe.
      While cryptococcosis and histoplasmosis do not share CT findings with COVID-19, there are overlapping radiographic signs between COVID-19 pneumonia, PCP, and IPA.
      Pneumocystis pneumonia is caused by ascomycetes fungi Pneumocystis jirovecii, formerly known as Pneumocystis carinii. The pathogen almost exclusively colonizes human lungs and causes clinical symptoms only in patients with weakened immune system.
      • Szydłowicz M.
      • Matos O.
      Pneumocystis pneumonia in the COVID-19 pandemic era: similarities and challenges.
      Typical CT findings differ from other fungal infections in that the predominant findings are GGOs with subpleural sparing
      • Duzgun S.A.
      • Durhan G.
      • Demirkazik F.B.
      • Akpinar M.G.
      • Ariyurek O.M.
      COVID-19 pneumonia: the great radiological mimicker.
      (Fig. 3A-B ) and “crazy paving”: patchy or geographic GGOs with smooth septal line thickening.
      • Orlowski H.L.P.
      • McWilliams S.
      • Mellnick V.M.
      • Bhalla S.
      • Lubner M.G.
      • Pickhardt P.J.
      • et al.
      Imaging Spectrum of invasive fungal and fungal-like infections.
      Thin-walled cystic lesions are commonly identified with CT,
      • Chong S.
      • Lee K.S.
      • Yi C.A.
      • Chung M.J.
      • Kim T.S.
      • Han J.
      Pulmonary fungal infection: imaging findings in immunocompetent and immunocompromised patients.
      appearing during the chronic phase of PCP in the areas previously affected by GGO and being responsible for pneumothorax development.
      • Chong S.
      • Lee K.S.
      • Yi C.A.
      • Chung M.J.
      • Kim T.S.
      • Han J.
      Pulmonary fungal infection: imaging findings in immunocompetent and immunocompromised patients.
      Other findings include pulmonary consolidation, interstitial markings, and adenopathy.
      • Orlowski H.L.P.
      • McWilliams S.
      • Mellnick V.M.
      • Bhalla S.
      • Lubner M.G.
      • Pickhardt P.J.
      • et al.
      Imaging Spectrum of invasive fungal and fungal-like infections.
      • Hsu J.M.
      • Hass A.
      • Gingras M.-A.
      • Chong J.
      • Costiniuk C.
      • Ezer N.
      • et al.
      Radiographic features in investigated for pneumocystis jirovecii pneumonia: a nested case-control study.
      Pleural effusions are extremely uncommon, and should prompt suspicion of another pathogen.
      • Orlowski H.L.P.
      • McWilliams S.
      • Mellnick V.M.
      • Bhalla S.
      • Lubner M.G.
      • Pickhardt P.J.
      • et al.
      Imaging Spectrum of invasive fungal and fungal-like infections.
      Fig. 3
      Fig. 3CT findings in different types of fungal pneumonia. A, B: axial and coronal views of GGOs (white arrows) with subpleural sparing (dark arrows) in 38-years-old man with PCP; C, D: axial and coronal views of cavitation with halo sign (white arrows) and crazy-paving sign (dark arrows) in 38-years-old woman with invasive pulmonary aspergillosis.
      Invasive pulmonary aspergillosis (two forms, angioinvasive and airway-invasive) has different findings depending on the disease stage. Typical CT findings include multiple ill-defined peripheral nodules that gradually coalesce into larger masses or areas of lobular to diffuse consolidation.
      • Chong S.
      • Lee K.S.
      • Yi C.A.
      • Chung M.J.
      • Kim T.S.
      • Han J.
      Pulmonary fungal infection: imaging findings in immunocompetent and immunocompromised patients.
      At the early stages of the disease the nodules are surrounded by a rim of ground-glass opacity, forming the halo sign
      • Chong S.
      • Lee K.S.
      • Yi C.A.
      • Chung M.J.
      • Kim T.S.
      • Han J.
      Pulmonary fungal infection: imaging findings in immunocompetent and immunocompromised patients.
      (Fig. 3C-D). The halo sign decreases over time, being replaced with cavitation, including the “air crescent sign”, which usually indicates good prognosis.
      • Orlowski H.L.P.
      • McWilliams S.
      • Mellnick V.M.
      • Bhalla S.
      • Lubner M.G.
      • Pickhardt P.J.
      • et al.
      Imaging Spectrum of invasive fungal and fungal-like infections.
      • Chong S.
      • Lee K.S.
      • Yi C.A.
      • Chung M.J.
      • Kim T.S.
      • Han J.
      Pulmonary fungal infection: imaging findings in immunocompetent and immunocompromised patients.
      Additionally, angioinvasive aspergillosis is associated with cavitation and pulmonary infarcts peripheral to the nodules.
      • Orlowski H.L.P.
      • McWilliams S.
      • Mellnick V.M.
      • Bhalla S.
      • Lubner M.G.
      • Pickhardt P.J.
      • et al.
      Imaging Spectrum of invasive fungal and fungal-like infections.
      • Chong S.
      • Lee K.S.
      • Yi C.A.
      • Chung M.J.
      • Kim T.S.
      • Han J.
      Pulmonary fungal infection: imaging findings in immunocompetent and immunocompromised patients.
      Airway-invasive pulmonary aspergillosis manifests on CT scans with patchy areas of consolidation and crazy paving with a peribronchial distribution and three-in-bud pattern.
      • Orlowski H.L.P.
      • McWilliams S.
      • Mellnick V.M.
      • Bhalla S.
      • Lubner M.G.
      • Pickhardt P.J.
      • et al.
      Imaging Spectrum of invasive fungal and fungal-like infections.
      • Chong S.
      • Lee K.S.
      • Yi C.A.
      • Chung M.J.
      • Kim T.S.
      • Han J.
      Pulmonary fungal infection: imaging findings in immunocompetent and immunocompromised patients.
      In rare cases, crazy-paving pattern can also be observed in patients with invasive aspergillosis
      • Philippot Q.
      • Cazes A.
      • Borie R.
      • Debray M.-P.
      • Danel C.
      • Hurtado Nedelec M.
      • et al.
      Secondary pulmonary alveolar proteinosis after lung transplantation: a single-Centre series.
      (Fig. 3C-D).

      3.4 Bacterial community-acquired pneumonia

      In the era of highly active antiretroviral therapy, bacterial community-acquired pneumonia (bCAP) remains a frequent clinical event: episodes of bCAP were observed in 2.1% of HIV-infected patients during a mean follow-up time of 16 months in the Strategies for Management of Antiretroviral Therapy trial.
      • Gordin F.M.
      • Roediger M.P.
      • Girard P.-M.
      • Lundgren J.D.
      • Miro J.M.
      • Palfreeman A.
      • et al.
      Pneumonia in HIV-infected persons.
      Even with antibacterial therapy, bCAP still represents an important cause of morbidity and mortality in HIV-infected individuals
      • Madeddu G.
      • Laura Fiori M.
      • Stella Mura M.
      Bacterial community-acquired pneumonia in HIV-infected patients.
      with mortality being in range between 6% and 15%,
      • Cillóniz C.
      • García-Vidal C.
      • Moreno A.
      • Miro J.M.
      • Torres A.
      Community-acquired bacterial pneumonia in adult HIV-infected patients.
      and morbidity of 0.53–0.56 cases/100 person-years.
      • Cillóniz C.
      • García-Vidal C.
      • Moreno A.
      • Miro J.M.
      • Torres A.
      Community-acquired bacterial pneumonia in adult HIV-infected patients.
      Bacterial pneumonia in HIV-infected patients is also associated with permanent decline in lung function, and a higher risk of lung cancer.
      • Shebl F.M.
      • Engels E.A.
      • Goedert J.J.
      • Chaturvedi A.K.
      Pulmonary infections and risk of lung cancer among persons with AIDS.
      The clinical presentation of pneumonia is usually the same as in the HIV-negative population; however, there is a tendency for rapid progression.
      • Waite S.
      • Jeudy J.
      • White C.S.
      Acute lung infections in Normal and immunocompromised hosts.
      Typical CT features include unilateral focal consolidation with air brochogram sign (Fig. 4A, B).
      • Waite S.
      • Jeudy J.
      • White C.S.
      Acute lung infections in Normal and immunocompromised hosts.
      • Yagihashi K.
      • Kurihara Y.
      • Fujikawa A.
      • Matsuoka S.
      • Nakajima Y.
      Correlations between computed tomography findings and clinical manifestations of Streptococcus pneumoniae pneumonia.
      Fig. 4
      Fig. 4Typical and COVID-19-mimicking CT findings for bacterial pneumonia. A, B: axial and coronal views showing unilateral lobar consolidation (arrows) in 44-years-old man with bacterial pneumonia; C, D: axial and coronal views of unilateral lobar GGOs with superimposed heterogenous consolidations (arrows) in 26-years-old man with bacterial pneumonia.
      Other CT features include cavitation,
      • Aviram G.
      • Fishman J.E.
      • Sagar M.
      Cavitary lung disease in AIDS: etiologies and correlation with immune status.
      pleural effusion and lymphadenopathy. GGOs may be present in the earliest course of the disease
      • Haroon A.
      • Higa F.
      • Fujita J.
      • Watanabe A.
      • Aoki N.
      • Niki Y.
      • et al.
      Pulmonary computed tomography findings in 39 cases of Streptococcus pneumoniae pneumonia.
      (Fig. 4C, D). Pleural empyema may be present in Staphylococcus aureus pneumonia.
      • Waite S.
      • Jeudy J.
      • White C.S.
      Acute lung infections in Normal and immunocompromised hosts.

      3.5 Pulmonary sarcoidosis

      Pulmonary sarcoidosis in HIV is rare
      • Synitsyn M.
      • Abu Arqoub T.
      • Barskiy B.
      • Plotkin D.
      • Reshetnikov M.
      • Galstyan A.
      Lung sarcoidosis in HIV infection: myth or reality?.
      ; moreover, HIV with persistent viremia is associated with lower risk of incident sarcoidosis in comparison with general population..
      • Hanberg J.S.
      • Akgün K.M.
      • Hsieh E.
      • Fraenkel L.
      • Justice A.C.
      Incidence and presentation of sarcoidosis with and without HIV infection.
      However, earlier studies suggest that sarcoidosis may be recurrent
      • Lenner R.
      • Teirstein A.S.
      • DePalo L.
      • Bregman Z.
      Recurrent pulmonary sarcoidosis in HIV-infected patients receiving highly active antiretroviral therapy.
      or newly diagnosed
      • Haramati L.B.
      • Lee G.
      • Singh A.
      • Molina P.L.
      • White C.S.
      Newly diagnosed pulmonary sarcoidosis in HIV-infected patients.
      in patients receiving HIV treatment. Further complicating the diagnosis, HIV treatment may induce sarcoidosis-like reactions,
      • Miedema J.
      • Nunes H.
      Drug-induced sarcoidosis-like reactions.
      requiring lesion biopsy to guide treatment. The CT features of newly diagnosed sarcoidosis in HIV patients resemble the findings in general population.
      • Haramati L.B.
      • Lee G.
      • Singh A.
      • Molina P.L.
      • White C.S.
      Newly diagnosed pulmonary sarcoidosis in HIV-infected patients.
      Unfortunately, pulmonary sarcoidosis has a wide spectrum of appearances in CT, earning “Great Pretender”
      • Hawtin K.E.
      • Roddie M.E.
      • Mauri F.A.
      • Copley S.J.
      Pulmonary sarcoidosis: the ‘Great pretender’.
      or “Master Mimicker”
      • Jameson A.
      • Revels J.
      • Wang L.L.
      • Wang D.T.
      • Wang S.S.
      Sarcoidosis, the master mimicker.
      monikers.
      Typical CT features are related to the lymphatics involvement and include hilar and mediastinal lymphadenopathy, upper- and middle-zone perilymphatic micro- and macronodules with subsequent fibrotic changes (Fig. 5).
      • Hawtin K.E.
      • Roddie M.E.
      • Mauri F.A.
      • Copley S.J.
      Pulmonary sarcoidosis: the ‘Great pretender’.
      Fig. 5
      Fig. 5Typical CT findings for pulmonary sarcoidosis. A: Axial view showing perilymphatic micronodules coalescing into micronodule in the right subpleural zone in 45-years-old man with sarcoidosis; B: coronal CT image of hilar lymphadenopathy (dark arrow) and perilymphatic micronodules (white arrow) in the same patient.
      Atypical CT features vary significantly and include GGOs, linear or miliary opacities, airspace consolidation, fibrocystic changes and pleural disorders.
      • Criado E.
      • Sánchez M.
      • Ramírez J.
      • Arguis P.
      • de Caralt T.M.
      • Perea R.J.
      • et al.
      Pulmonary sarcoidosis: typical and atypical manifestations at high-resolution CT with pathologic correlation.

      3.6 Lung cancer

      HIV-positive individuals have 1.7-fold increased lung cancer risk in comparison with the general population.
      • Sigel K.
      • Wisnivesky J.
      • Gordon K.
      • Dubrow R.
      • Justice A.
      • Brown S.T.
      • et al.
      HIV as an independent risk factor for incident lung cancer.
      Clinical and radiographic characteristics are similar between HIV infected and uninfected patients.
      • Sigel K.
      • Makinson A.
      • Thaler J.
      Lung cancer in persons with HIV.
      However, lung cancer in HIV infected patients is more aggressive and develops at younger age compared with uninfected patients.
      • Javadi S.
      • Menias C.O.
      • Karbasian N.
      • Shaaban A.
      • Shah K.
      • Osman A.
      • et al.
      HIV-related malignancies and mimics: imaging findings and management.
      • Makinson A.
      • Eymard-Duvernay S.
      • Raffi F.
      • Abgrall S.
      • Bommart S.
      • Zucman D.
      • et al.
      Feasibility and efficacy of early lung cancer diagnosis with chest computed tomography in HIV-infected smokers.
      Lung cancer lesions occur more frequently in the upper lobes, with a predilection for the right lung.
      • MacMahon H.
      • Naidich D.P.
      • Goo J.M.
      • Lee K.S.
      • Leung A.N.C.
      • Mayo J.R.
      • et al.
      Guidelines for Management of Incidental Pulmonary Nodules Detected on CT images: from the fleischner society 2017.
      However, the distribution could arise from the fact that perihilar and paramediastinal regions can be difficult to evaluate.
      • Hossain R.
      • Wu C.C.
      • de Groot P.M.
      • Carter B.W.
      • Gilman M.D.
      • Abbott G.F.
      Missed lung cancer.
      As a result, most missed parenchymal lesions tend to locate in the lower lobes.
      • White Charles S.M.
      • Salis Ari I.
      • Meyer C.A.
      Missed lung cancer on chest radiography and computed tomography.
      By the location of the primary lesions, lung cancers can be categorized as central type or peripheral type.
      • Silvestri G.A.
      • Gonzalez A.V.
      • Jantz M.A.
      • Margolis M.L.
      • Gould M.K.
      • Tanoue L.T.
      • et al.
      Methods for staging non-small cell lung cancer.
      Unfortunately, there is ambiguity about what to consider a “centrally located” tumor, causing a lack of agreement between physicians and unnecessary invasive staging for some patients.
      • Casal R.F.
      • Vial M.R.
      • Miller R.
      • Mudambi L.
      • Grosu H.B.
      • Eapen G.A.
      • et al.
      What exactly is a centrally located lung tumor? Results of an online survey.
      Non-calcified pulmonary nodules are typical computed tomography findings associated with early stages of lung cancer. Depending on the attenuation values, lung lesions can be classified as solid (Fig. 6A-B ) and subsolid (Fig. 6C-D) nodules. Subsolid nodules include both pure ground-glass nodules and mixed part-solid (halo) types. Consolidation is also frequent on lung cancer CT scans.
      • Furuya K.
      • Yasumori K.
      • Takeo S.
      • Sakino I.
      • Uesugi N.
      • Momosaki S.
      • et al.
      Lung CT: part 1, mimickers of lung cancer???Spectrum of CT findings with pathologic correlation.
      It has been proposed that lung cancer with a consolidation <50% of the maximum tumor diameter could be a valuable predictive factor for early lung cancer.
      • Ohde Y.
      The proportion of consolidation to ground-glass opacity on high resolution CT is a good predictor for distinguishing the population of non-invasive peripheral adenocarcinoma.
      However, the threshold was derived from retrospective studies; prospective study of Suzuki et al. proposed a consolidation-to-tumor ratio of ≤25% as a factor associated with early lung cancer.
      • Suzuki K.
      • Koike T.
      • Asakawa T.
      • Kusumoto M.
      • Asamura H.
      • Nagai K.
      • et al.
      A prospective radiological study of thin-section computed tomography to predict pathological noninvasiveness in peripheral clinical IA lung cancer (Japan clinical oncology group 0201).
      which was confirmed in later studies.
      • Xi J.
      • Yin J.
      • Liang J.
      • Zhan C.
      • Jiang W.
      • Lin Z.
      • et al.
      Prognostic impact of radiological consolidation tumor ratio in clinical stage ia pulmonary ground glass opacities.
      • Snoeckx A.
      • Reyntiens P.
      • Carp L.
      • Spinhoven M.J.
      • El Addouli H.
      • Van Hoyweghen A.
      • et al.
      Diagnostic and clinical features of lung cancer associated with cystic airspaces.
      Fig. 6
      Fig. 6Typical CT findings for lung cancer. A, B: axial and coronal views of solid nodule (arrows) in 78-year-old woman with early-stage lung cancer; C, D: axial and coronal views of subsolid nodule in the same patient; E: axial CT image showing large soft-tissue mass invading pericardium (dark arrow) and right-sided pleural effusion (white arrow) in 65-year-old man with advanced lung cancer; F: coronal view showing large hilar soft-tissue mass (dark arrow) and perifocal infiltrative changes (white arrow) in the same patient.
      Rarer manifestations of early lung cancer are single or multiple “cystlike” airspaces with areas of consolidation or ground glass abutting the wall of the cystic part or interspersed between the cystic components.
      • Snoeckx A.
      • Reyntiens P.
      • Carp L.
      • Spinhoven M.J.
      • El Addouli H.
      • Van Hoyweghen A.
      • et al.
      Diagnostic and clinical features of lung cancer associated with cystic airspaces.
      Typical presentations of advanced lung cancer stages are nodules and masses larger than 4 cm, with invasion into adjacent central/mediastinal or peripheral structures and involvement of lymph nodes/metastasis (Fig. 6E-F).
      • Levin G.A.
      • Gavrilov P.V.
      • Mosina N.V.
      • Mosin I.V.
      • Sokolovich E.G.
      The difficulties of diagnostics of the tuberculosis and lung cancer combination.
      • Detterbeck F.C.
      • Boffa D.J.
      • Kim A.W.
      • Tanoue L.T.
      The eighth edition lung cancer stage classification.
      Other common findings observed on the later stages are obstructive pneumonia and atelectasis
      • Bulbul Y.
      • Eris B.
      • Orem A.
      • Gulsoy A.
      • Oztuna F.
      • Ozlu T.
      • et al.
      Pulmonary atelectasis and survival in advanced non-small cell lung carcinoma.
      and pleural effusion
      • Psallidas I.
      • Kalomenidis I.
      • Porcel J.M.
      • Robinson B.W.
      • Stathopoulos G.T.
      Malignant pleural effusion: from bench to bedside.
      (Fig. 6E-F).

      4. Discussion

      This pictorial review summarizes the current literature on nonenhanced chest CT findings resembling COVID-19-associated pneumonia that can be observed in HIV infected patients. For PLHIV, we identified five major COVID-19-mimicking disease groups: viral pneumonia, fungal pneumonia, bacterial pneumonia, sarcoidosis, and lung cancer (see Fig. 1).
      Bilateral ground glass opacities and subpleural involvement are common in COVID-19 pneumonia (see Fig. 2C-D). Less frequent findings are crazy paving sign, coalescent consolidations, subpleural lines, and pleural effusions.

      4.1 Differences between COVID-19 and other viral pneumonias

      Patchy, multifocal, or diffuse GGOs are typical CT findings associated with viral pneumonia (see Fig. 2A-B); the main distinguishing pattern observed in COVID-19 is the apicobasal or peripheral distribution of ground glass opacities (see Fig. 2C-D, A-B). Findings that are common for viral pneumonias and uncommon in COVID-19 pneumonia, appearing only in severe COVID-19, include interlobular septal or bronchial wall thickening, and patchy, multifocal consolidation that can progress with the disease course.
      Bilateral GGOs are typical both for COVID-19 and CMV pneumonia, but the latter has basal GGO distribution with subpleural sparing accompanied by small centrilobular nodules (see Fig. 2C-D, E-F).

      4.2 Differentiating between fungal, viral pneumonias, and COVID-19

      There are no typical CT findings associated with fungal pneumonias, but each of the four most common IFIs in PLHIV has its own set of characteristic features. The CT features of PCP are similar to the coronavirus infection, however GGOs in PCP are usually extensive and predominate in a central distribution with subpleural sparing (see Fig. 2C-D, Fig. 3A-B). The other distinctive CT features of PCP are interstitial markings; chronic phase of PCP is often associated with occurrence of thin-walled cystic lesions.
      Invasive pulmonary aspergillosis in HIV infected patients appears at early stages as multiple ill-defined peripheral nodules surrounded by halo sign. With the progress of IPA, halo sign decreases, being replaced first by the hypodense sign, and then by the air crescent sign (see Fig. 3C-D). Meanwhile, the nodules gradually coalesce into larger masses or areas of lobular or diffuse consolidation (see Fig. 3C-D).

      4.3 The non-specific features of bacterial pneumonia

      The CT findings in acute histoplasmosis and bacterial pneumonia are very similar, consisting of acute consolidation and lymphadenopathy (see Fig. 4). The presence of calcified pulmonary nodules is highly suggestive of current or previous histoplasmosis, while in bacterial pneumonia consolidations gradually disappear with patient's recovery.

      4.4 Adding sarcoidosis and lung cancer to the list

      The characteristic CT findings seen in pulmonary sarcoidosis, distinguishing it from viral, fungal, and bacterial pneumonias, include symmetric hilar and mediastinal adenopathy, and well-defined nodules 2–5 mm in size, with a perilymphatic distribution along the bronchovascular bundles, interlobular septa, interlobar fissures, and subpleural regions (see Fig. 5).
      Findings associated with lung cancer include non-calcified solid and subsolid pulmonary nodules, the size of which depends on the stage of the disease (see Fig. 6). The nodule persistence during few weeks follow-up is a strong diagnostic sign of lung cancer. Advanced lung cancer manifests on CT scans with obstructive pneumonia, atelectasis, and pleural effusion (see Fig. 6E, F).

      4.5 For immunocompromised patients, a different diagnostic approach is needed

      Several CT findings observed in immunocompromised patients are not pathognomonic for the same diseases in immunocompetent population. For example, cryptococcosis manifests in immunocompetent patients with multiple well-defined nodules, which are uncommon in immunocompromised hosts. Infections such as cryptococcosis, PCP, pulmonary candidiasis occur predominantly in immunocompromised patients.
      • Chong S.
      • Lee K.S.
      • Yi C.A.
      • Chung M.J.
      • Kim T.S.
      • Han J.
      Pulmonary fungal infection: imaging findings in immunocompetent and immunocompromised patients.
      When the CT signs associated with these pathologies appear in immunocompetent hosts, they may be caused by other conditions, such as malignancy, inflammatory noninfectious pulmonary disease, COVID-19, and iatrogenic disease.
      • Yagihashi K.
      • Kurihara Y.
      • Fujikawa A.
      • Matsuoka S.
      • Nakajima Y.
      Correlations between computed tomography findings and clinical manifestations of Streptococcus pneumoniae pneumonia.
      Detailed clinical information should be provided to the radiologist for the optimal interpretation of the CT scans. When nodules are detected on CT images, follow-up scans are a useful tool to determine therapy changes, specify the diagnosis, and rule out lung cancer.

      4.6 Imaging significance and complications

      According to retrospective study of Kowalska et al., the presence of typical or atypical radiological changes is associated with poor prognosis for HIV infected patients with COVID-19 coinfection.
      • Kowalska J.D.
      • Bieńkowski C.
      • Fleischhans L.
      • Antoniak S.
      • Skrzat-Klapaczyńska A.
      • Suchacz M.
      • et al.
      The presence of either typical or atypical radiological changes predicts poor COVID-19 outcomes in HIV-positive patients from a multinational observational study: data from euroguidelines in central and Eastern Europe network group.
      Findings such as consolidation, nodules, cysts, and spontaneous pneumothorax occurring in the course of COVID-19 should raise the suspicion of secondary infection, and HIV-positive patients should undergo a broad differential diagnosis 106.
      • Kowalska J.D.
      • Bieńkowski C.
      • Fleischhans L.
      • Antoniak S.
      • Skrzat-Klapaczyńska A.
      • Suchacz M.
      • et al.
      The presence of either typical or atypical radiological changes predicts poor COVID-19 outcomes in HIV-positive patients from a multinational observational study: data from euroguidelines in central and Eastern Europe network group.
      Primary coinfections in COVID-19 are rare.
      • Rovina N.
      • Koukaki E.
      • Romanou V.
      • Ampelioti S.
      • Loverdos K.
      • Chantziara V.
      This is also true for HIV-positive patients; to date, there have been only case reports published on concomitant COVID-19, HIV, and other disease, typically represented by fungal pneumonia or tuberculosis.
      • Bongomin F.
      • Sereke S.G.
      • Okot J.
      • Katsigazi R.
      • Kiiza Kandole T.
      • Oriekot A.
      • et al.
      COVID-19, HIV-associated cryptococcal meningitis, disseminated tuberculosis and acute ischaemic stroke: a fatal foursome.
      • Broadhurst A.G.B.
      • Lalla U.
      • Taljaard J.J.
      • Louw E.H.
      • Koegelenberg C.F.N.
      • Allwood B.W.
      The diagnostic challenge of pneumocystis pneumonia and COVID-19 co-infection in HIV.
      However, when there is a lack of clinical improvement, unusual CT findings can hint on the probability of secondary infection. For example, results of Wu et al. suggest considering the coexistence of PCP with other infection when pleural effusion was present in an immunocompromised patient.
      • Wu H.-Y.
      • Wu K.-S.
      • Huang Y.-L.
      • Dai S.-H.
      • Chang D.-Y.
      • Kuo S.-H.
      • et al.
      Identifying predictors for bacterial and fungal coinfection on chest computed tomography in patients with pneumocystis pneumonia.
      Our review provides a list of typical and rare findings for each of the disease groups included, which may assist in the detection of such cases.

      4.7 Limitations of the review

      First, due to several occasions of conflicting data in the published literature, we have not included into review the CT features of the diseases that were reported in some papers and not mentioned in other studies. This could potentially lead to some rare but specific CT signs not being mentioned in the proposed list. However, the listing of all rare findings would significantly and unnecessary complicate the data provided in the review. Second, due to peculiarities of the URIS architecture, we have had limited access to the clinical and demographic data of the CT studies used as illustrated material for the review. Because of that, we could not find examples of cases associated with rare combinations of confirmed pathologies. However, we have provided the references to the published literature containing relevant high-quality imaging data.

      5. Conclusion

      In the COVID-19 era, HIV patients with pulmonary diseases should undergo a broad differential diagnosis including viral pneumonia (with the careful attention on COVID-19 and CMV), fungal pneumonia (prioritizing PCP and invasive aspergillosis), bacterial pneumonia, sarcoidosis, and lung cancer. Follow-up scans for the assessment of radiological changes are a useful tool to specify the diagnosis and predict the outcomes for the patients. The appearance of unusual findings on chest CT suggests considering the coexistence of primary pathology with secondary infection. This review provides radiologists with carefully selected non-conflicting descriptive and pictorial data that may assist the diagnostic decision making.

      CRediT authorship contribution statement

      Liya R. Abuladze: conceptualization, methodology, writing, visualization, investigation. Ivan A. Blokhin: conceptualization, methodology, writing, visualization, investigation. Anna P. Gonchar: conceptualization, methodology, writing, visualization, investigation. Mariya M. Suchilova: writing, editing. Anton V. Vladzimirskyy: reviewing and editing, supervision. Victor A. Gombolevsky: reviewing and editing, supervision. Eleonora A. Balanyuk: supervision. Oksana G. Ni: supervision. Dmitry V. Troshchansky: supervision. Roman V. Reshetnikov – data curation, writing, reviewing, editing, and supervision.

      Acknowledgments

      The authors would like to thank Prof. Sergey P. Morozov for his invaluable time and expertise. We are also grateful to Dr. Pavel V. Gavrilov for his contribution to the project.

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