Pneumonitis and Pulmonary Mucormycosis in a Covid-19 Positive Patient—A Case Report

Abstract

In the wake of second wave of coronavirus disease (Covid-19), an increased number of mucormycosis cases were reported by the Ministry of Health and Family Welfare in India. A total of 45 432 cases of mucormycosis were reported till mid-July 2021, with 4252 fatalities. Mucormycosis and other fungal infections are most commonly seen as an opportunistic infection. They are found in those with low underlying immunity either due to a diabetes, cancers particularly hematological malignancies, and so on, or as a side effect of prolonged/irrational use of certain drugs like steroids, immunosuppressive drugs for management of other disorders including Covid-19. The Health Authorities in India stated that although it is not a new disease, its true incidence during the beginning of the second wave was unknown as it was not a notifiable disease. As per reports, the most common presentations of mucormycosis included rhinocerebral (77.6%), cutaneous (4.3%), and pulmonary (3.0%). We present a case of pulmonary mucormycosis and pneumonitis in a Covid-19 positive patient brought for autopsy. The patient was an under trial prisoner sent for treatment to our facility who was reported Covid positive.

Introduction

Mucormycosis (previously called zygomycosis) is a rare but serious angioinvasive infection caused by a group of fungi called mucormycetes. Spores of these ubiquitous fungi (commonly found in soil, fallen leaves, compost, animal dung, and air) can be inhaled and then infect the lungs, sinuses, and extend into the brain and eyes. Less often, infection may develop when the spores enter the body through a cut or an open wound. Mucormycosis is not a contagious disease, it cannot spread from one person to another.

Mucormycosis mainly affects people who are immunocompromised, or patients already infected with other diseases. High-risk groups include people with diabetes (especially diabetic ketoacidosis), solid organ transplantation, neutropenia (low neutrophils, a type of white blood cells), long-term systemic corticosteroid use, and iron overload (hemochromatosis). The risk is high for people living with HIV, and those using immuno-modulating drugs, including the anti-fungal voriconazole in some high-risk groups.

Clinical presentation is classified according to the organ involvement. It can be rhino-orbital cerebral, pulmonary, cutaneous, gastrointestinal, or disseminated.

Mucormycosis is an aggressive, life-threatening infection requiring prompt diagnosis and early treatment. Treatment usually consists of antifungal medications and surgery. Generally, these fungi aren’t harmful to most people. However, for people who have weakened immune systems, breathing in mucormycete spores can cause an infection in the lungs or sinuses which can spread to other parts of the body (1).

Since December 2019, the ongoing pandemic of coronavirus disease 2019 (Covid-19) has been a global cause of widespread immunodeficiency. In 2021, a surge was reported in mucormycosis in cases with Covid-19 as a rare but serious complication of Covid-19. Cases of rhino-orbital or pulmonary mucormycosis were being reported in India, especially during the second wave of Covid-19. Mucor infection may occur during Covid-19 infection or a few weeks after recovery from Covid-19 (2).

Covid-19 is an infectious disease caused by the SARS-CoV-2 virus. In December 2019, a pneumonia outbreak was reported in Wuhan, China. On December 31, 2019, the outbreak was traced to a novel strain of coronavirus, which was given the interim name 2019-nCoV by the World Health Organization, later renamed SARS-CoV-2 by the International Committee on Taxonomy of Viruses.

As of September 8, 2021, there have been at least 4 586 188 confirmed deaths and more than 221 936 765 confirmed cases in the Covid-19 pandemic. The Wuhan strain has been identified as a new strain of Betacoronavirus from group 2B with approximately 70% genetic similarity to the SARS-CoV (2).

Mucormycosis can occur among Covid-19 patients, especially with poor glycemic control, widespread and injudicious use of corticosteroids and broad-spectrum antibiotics, and invasive ventilation. Owing to the high mortality, high index of suspicion is required to ensure timely diagnosis and appropriate treatment in high-risk populations (3).

During the second wave of Covid-19 in India which struck in April 2021, there was a sudden increase in the number of mucormycosis cases as reported by the Ministry of Health & Family Welfare, Government of India. A total of 45 432 cases of mucormycosis were reported in India till mid-July 2021, with 4252 fatalities. Most of these cases were reported in concomitant Covid-19 patients. Of the total number of mucormycosis patients, 34 940 had Covid, 26 187 had the comorbidity of diabetes, and 21 523 were on steroids.

Case Report

The patient was a 72-year-old male who was a prisoner in a jail serving his sentence. The patient complained of breathlessness and was taken to the prison hospital where his SpO2 was 69%. He was then shifted to our facility for management where he was admitted. His SpO2 on admission was 84%; he was sick, dehydrated with blood pressure 100/60 mm of Hg. Rapid antigen test for Covid-19 was done which was positive. He was shifted to the Covid isolation ward. On examination, his heart sounds were normal with no murmur. Bilateral air entry was present with rhonchi. He had a history of right-sided Cerebro-vascular Accident (CVA) two years back and was a known case of ischemic heart disease. Oxygen was started, and on the second day of admission the SpO2 was 96% on oxygen. High Resolution Computed Tomography (HRCT) thorax and Non Contrast Computerised Tomography (NCCT) head were planned but could not be done as the patient was disorientated. The next two days were uneventful. On the fifth day, the patient got suddenly unresponsive with unrecordable Blood pressure (BP), Pulse rate (PR) and SpO2 at 6.30 am in the morning. Cardiopulmonary resuscitation was started but the patient expired after 20 minutes. Reverse Transcription Polymerase Chain Reaction (RTPCR) sample had been taken the same day for testing for Covid-19. The RTPCR sample was negative. The dead body was then sent for autopsy as a custodial death case under section 176 of the Criminal Procedure Code, India, as per law as he was a prisoner.

Autopsy Findings

The autopsy on the dead body was conducted in the segregated Covid-19 mortuary following all Covid-19 autopsy protocols as issued by the Government. The dead body was received packed in a white colored body bag and further in a white sheet.

The brain was congested, edematous, and softened in consistency. It was preserved for histopathological examination. On opening the chest cavity, the lungs were found to be adhered to the chest wall and had vaguely geographic, mottled discoloration on the external surfaces. Both lungs were deeply congested on cut section. There was hemorrhagic consolidation of both the lungs ( Figure 1 ). The heart was adhered to the pericardium. The stomach contained about 50 cc of brownish mucoid serous fluid. The gastric mucosa was congested at places. The liver, spleen, and both kidneys were deeply congested on cut section. Both lungs, the heart, a portion of the liver, a portion of the spleen and portions of both kidneys were preserved and sent for histopathological examination while the stomach, segments of both small and large intestines, portion of spleen, portion of the liver, and portions of both kidneys were preserved and sent for chemical analysis.

Figure 1:

Photograph of the lungs on autopsy showing both adhered to the chest wall. Congested on cut section.

The chemical analysis of viscera was negative for any common poison. However, the histopathological examination of the lungs revealed pneumonitis ( Figure 2 ) along with innumerable angioinvasive hyphae, with involvement of medium to small caliber arteries ( Figure 3 ). The hyphae were large, ribbon-like, and pauciseptate, consistent with a mucormycete ( Figure 4 ; Hematoxylin and eosin), which was confirmed on a Sabouraud’s Dextrose Agar culture.

Figure 2:

Low power view 10× showing pneumonia (Hematoxylin and eosin).

Figure 3:

Low power 10× showing neutrophilic infiltrate along with edema in the alveoli along with mucormycosis (Hematoxylin and eosin).

Figure 4:

High power view 40× showing mucormycosis. Periodic Acid Schiff (PAS) stained slide.

Discussion

Mucormycosis is a life-threatening infection that occurs in patients who are immunocompromised because of diabetic ketoacidosis, neutropenia, organ transplantation, and/or increased serum levels of available iron. Because of the increasing prevalence of diabetes mellitus, cancer, and organ transplantation, the number of patients at risk for this deadly infection is increasing. Despite aggressive therapy, which includes disfiguring surgical debridement and frequently adjunctive toxic antifungal therapy, the overall mortality rate is high (4). It is an infection caused by fungi belonging to the order Mucorales (5).

Rhizopus oryzae is the most common organism isolated from patients with mucormycosis and is responsible for ∼70% of all cases of mucormycosis. The major risk factors for mucormycosis include uncontrolled diabetes mellitus in ketoacidosis, other forms of metabolic acidosis, treatment with corticosteroids, organ or bone marrow transplantation, neutropenia, trauma and burns, malignant hematologic disorders, and deferoxamine therapy in patients receiving hemodialysis (6).

Clinical and experimental data clearly demonstrate that individuals who lack phagocytes or have impaired phagocytic function are at higher risk of mucormycosis. For example, severely neutropenic patients are at increased risk for developing mucormycosis. In contrast, patients with AIDS do not seem to be at increased risk for developing mucormycosis. These findings suggest that neutrophils, but not necessarily T lymphocytes, are critical for inhibiting fungal spore proliferation. (Sugar AM. Agents of mucormycosis and related species (7)).

The prognosis of mucormycosis is relatively poor especially when the host is immunocompromised and when the diagnosis is delayed. The overall survival rates of rhinocerebral disease (50%) are far better than its pulmonary and disseminated counterparts partly because of its early diagnosis (8).

Although the clinical characteristics of mucormycosis are well established, infection can be difficult to diagnose antemortem, resulting in frequent postmortem diagnoses. Despite this, the gross appearance of mucormycosis at autopsy has not been well described. Autopsy examination has demonstrated characteristic hemorrhagic infarcts with a targetoid appearance in the affected organs. These findings are secondary to fungal angioinvasion with subsequent thrombosis and tissue necrosis. Mucormycosis should be suspected at autopsy when these characteristic infarcts are identified within the proper clinical context, and a high suspicion for atypical infections should be maintained postmortem in immunosuppressed patients (9).

There was diffuse petechial hemorrhage and dark red mottled discoloration of the lungs. Multiple wedge-shaped infarcts were identified. Internal examination revealed diffuse petechial hemorrhages and dark red mottled discoloration of the pulmonary parenchyma. There were multiple pale, wedge-shaped, cavitary infarcts in the left lung. The peritoneal cavity contained 1800 mL of dark yellow-brown translucent fluid (10).

Autopsy has been referred to as the gold standard for diagnosis of mucormycosis given that the disease can be challenging to diagnose clinically; for example, only 25% of gastrointestinal mucormycosis is estimated to be diagnosed antemortem (10).

Zurl et al report the case of a 53-year-old male patient with secondary acute myeloid leukemia (AML) who suffered from Covid-19 Acute Respiratory Distress Syndrome (ARDS) and was diagnosed postmortem with mucormycosis. This patient was diagnosed with secondary AML and was transferred to hospital for further treatment. Medical history included myelodysplastic syndrome, obesity (body mass index 34), and depression. Polymerase chain reaction (PCR) for SARS-CoV-2 from a nasopharyngeal swab was performed and revealed a positive result. Hemodynamic situation worsened within the next days, and the patient died on day 24 after symptoms onset. A full autopsy was performed, and microscopy of lung tissue showed tissue invasive nonpigmented fungal hyphae. To specify the fungal pathogen, internal transcribed spacer sequencing from lung tissue was performed and revealed fungal DNA 100% homologous to Rhizopus microsporus. Thus, the patient was diagnosed postmortem with invasive pulmonary mucormycosis due to Rhizopus microsporus with no signs of dissemination. SARS-CoV-2 PCR from a throat swab performed postmortem was positive with a cycle threshold of 28, whereas PCR from lung tissue was negative (11).

Kula et al systematically reviewed autopsy series of three or more decedents with Covid-19 for evidence of invasive mold disease (IMD). They searched PubMed, Web of Science, OVID (Embase), and medRxiv for studies in English or French published from January 1, 2019, to September 26, 2020. They identified 1070 references, of which 50 studies met the criteria. These studies described autopsies from 677 decedents, with individual-level data for 443 decedents. Autopsy-proven IMD occurred in 11 (2%) of 677 decedents, including eight Corrective action & Preventive action (CAPA), two unspecified IMD, and one disseminated mucormycosis. They concluded that IMD, including CAPA, is an uncommon autopsy finding in Covid-19 (12).

Dilek et al reported a patient who developed mucormycosis during post-Covid period. They also searched literature to describe the incidence, clinical features, and outcomes of Covid-19-associated mucormycosis in a 100 patients of which majority of the reports were from India (68). They report that the diagnosis was established postmortem in two cases (13).

Toyama et al report a case of a 58-year-old man with diabetes and idiopathic pulmonary fibrosis presented with fever and dyspnea for three days. His Covid-19 antigen test result was positive. On admission, he developed severe acute respiratory failure with bilateral pneumonia. He was intubated and started on intravenous remdesivir, dexamethasone, methylprednisolone, and tocilizumab. He died of multiple organ failure 30 days after the transfer to our hospital. Autopsy revealed necrotic nodules, thromboangitis, and hemorrhage infarction in multiple organs including brain, lung, heart, adrenal gland, and kidney. Many filamentous fungi with prominent infiltration of neutrophils were observed intravascularly in these organs. Grocott strain and genetic analysis revealed that the fungi belong to Rhizopus microsporus group. They concluded that he died of sepsis and multiple organ failure due to disseminated mucormycosis (14).

Conclusion

Clinical or medico-legal autopsy is a necessary medical tool not only for quality assurance and training to the medical professionals but also to enhance the understanding of diseases, especially in unknown and emerging diseases such as pandemic Covid-19. Autopsy examinations are of paramount importance to gain a better knowledge of the underlying Pathophysiological chances and disease-associated findings in different organs involved. Teamwork with the combined efforts of Forensic Medicine, Pathology, and Microbiology are surely to bring positive outcomes of our understanding of such novel and widespread pandemics.

AUTHORS

Luv Sharma MD, Department of Forensic Medicine, Pt. B.D. Sharma Post Graduate Institute of Medical Sciences

Roles: Project conception and/or design, data acquisition, analysis and/or interpretation, manuscript creation and/or revision, approved final version for publication, accountable for all aspects of the work, principal investigator of the current study, general supervision, general administrative support

Sumiti Gupta MD, Department of Pathology, Pt. B.D. Sharma Post Graduate Institute of Medical Sciences

Roles: Data acquisition, analysis and/or interpretation, approved final version for publication, general supervision

Lalit Chopra MD, Department of Forensic Medicine, Pt. B.D. Sharma Post Graduate Institute of Medical Sciences

Roles: Project conception and/or design

Pooja Dhamija MD, Department of Pathology, Pt. B.D. Sharma Post Graduate Institute of Medical Sciences

Roles: Data acquisition, analysis and/or interpretation, writing assistance and/or technical editing