The Reemergence of Measles: What Every Pathologist Needs to Know

Abstract

Objectives

Present-day pathologists may be unfamiliar with the histopathologic features of measles, which is a reemerging disease. Awareness of these features may enable early diagnosis of measles in unsuspected cases, including those with an atypical presentation. Using archived tissue samples from historic patients, a unique source of histopathologic information about measles and other reemerging infectious diseases, we performed a comprehensive analysis of the histopathologic features of measles seen in commonly infected tissues during prodrome, active, and late phases of the disease.

Methods

Subspecialty pathologists analyzed H&E-stained slides of specimens from 89 patients accessioned from 1919 to 1998 and correlated the histopathologic findings with clinical data.

Results

Measles caused acute and chronic histopathologic changes, especially in the respiratory, lymphoid (including appendix and tonsils), and central nervous systems. Bacterial infections in lung and other organs contributed significantly to adverse outcomes, especially in immunocompromised patients.

Conclusions

Certain histopathologic features, especially Warthin-Finkeldey cells and multinucleated giant cells without inclusions, allow pathologists to diagnose or suggest the diagnosis of measles in unsuspected cases.

KEY POINTS

• Measles is reemerging as a result of vaccine hesitancy and political crises. Most pathologists today are unfamiliar with the histopathologic features of measles.

• Pathologists can make an early diagnosis of measles, minimizing spread. Knowing the central nervous system findings benefits patients with mysterious neurologic symptoms years after recovery.

• Historic archived tissue from the Joint Pathology Center (formerly the Armed Forces Institute of Pathology) provides a unique source of educational material.

INTRODUCTION

A rubeola (measles) vaccine became available in 1963; before then, infection was nearly ubiquitous during childhood. According to the Centers for Disease Control and Prevention, before the vaccine became available, approximately 3 to 4 million people were infected per year in the United States; of these, an estimated 48,000 required hospitalization, 1,000 developed encephalitis, and 400 to 500 died.^1-3 Widespread vaccination resulted in disease elimination in the United States in 2000 except for rare, imported cases and isolated outbreaks in unvaccinated communities; most countries in the developed world have had a similar experience. Consequently, most pathologists practicing today in industrialized nations have little or no experience with measles.

Measles is reemerging in the United States and other nations. The causes of the increase in the percentage of unvaccinated people in developed countries include vaccine hesitancy, decreased well-child visits during the coronavirus disease 2019 pandemic, and decreased vaccination rates among immigrants and travelers from countries with dysfunctional health care systems exacerbated by poverty, refugee crises, political instability, and climate change.^4-8 Familiarity with the histopathologic findings in measles enables pathologists to make an early diagnosis of measles in unsuspected cases. For example, diagnostic viral cytopathic changes may be observed in a child’s appendectomy or tonsillectomy specimen before the appearance of a rash, Koplik spots, or conjunctivitis FIGURE 1 (Supplemental Figures 1 and 2; all supplemental materials can be found at American Journal of Clinical Pathology online), allowing earlier isolation to prevent infection among contacts. Also, characteristic histopathologic features may be identified in surgical or autopsy specimens from immunosuppressed individuals who did not mount an adequate antibody response and, therefore, did not develop a rash.⁹ Our institution is a unique resource for analysis of the histopathology of measles because of the availability of numerous historical specimens and the cooperative efforts of subspecialists.

FIGURE 1

Patient with characteristic rash of measles and cough.

MATERIALS AND METHODS

A search of the repository database for all cases coded as measles, rubeola, Koplik spot, or subacute sclerosing panencephalitis from 1864 to 1998 identified 350 specimens from 319 patients. Patients with German measles were excluded. Patients whose clinical history included childhood measles but for whom measles had no relevance to the specimen were excluded. Of the remaining 270 patients, 89 with complete medical records and high-quality blocks or slides were selected for study. Records were reviewed for year, sex, age, geographic location, military service, and relevant clinical data (Supplemental Tables 1 and 2). H&E-stained slides were reviewed for viral cytopathic changes, including the presence of Warthin-Finkeldey cells (WFCs), defined as multinucleated cells with eosinophilic nuclear inclusions pathognomonic of measles,¹⁰ and multinucleated giant cells (MGCs), by infectious disease pathology experts (F.A.N. and R.C.N.) and for other histopathologic changes by appropriate subspecialists (Supplemental Table 3). Histopathologic features were correlated with clinical phase. RNAScope assay (Advanced Cell Diagnostics) amplification and in situ hybridization using a measles virus probe was performed on 16 of the most recent specimens using measles virus–transfected and untransfected neuroblastoma cell line cells as controls.¹¹ Transmission electron microscopy was performed on an autopsy lung tissue block.

RESULTS

Demographic and Clinical Features

Of the 89 patients whose cases were selected, 53% were male, 33% were female, and 16% were of unknown sex. Ages ranged from 5 months to 74 years, with a mean (SD) age of 12 (14) years. Patients were from the United States, Canada, Europe, Asia, Africa, and Latin America. Sixty-nine percent of the patients were autopsied. Time from the onset of measles symptoms to death ranged from 1 to 30 days, with a mean time span of 11 days (mode, 5 days) among deceased patients.

Microscopic Features

WFCs or MGCs were seen in specimens from 49 (55%) patients; among these patients, 17 (35%) had tissue specimens showing WFCs, 25 (51%) showing MGCs, and 7 (14%) showing both histopathologic features. Multinucleated lymphoid cells (MLCs) were seen in thymus and lymph node. The tissues in which WFCs, MGCs, or MLCs were seen are listed by phase in TABLE 1 and in more detail in Supplemental Table 4. In lung, the most common finding was airway-centered inflammation, which included variable degrees of neutrophilic or mononuclear infiltrates within small airway lumens, in the interstitium, or within alveolar spaces. WFCs tended to be within alveolar spaces FIGURE 2A. Rarely, there were MGCs within airway epithelium without inflammation. MGCs were especially abundant in lung sections from patients with human immunodeficiency virus (HIV) (Supplemental Figure 3). Even in specimens from immunocompetent patients there was often evidence of bacterial infection such as suppurative or fibrinous pleuritis or acute bronchopneumonia. Diffuse alveolar damage, characterized by hyaline membranes, squamous metaplasia, and septal edema FIGURE 2B, was most frequent in those patients with an underlying disease, such as Langerhans cell histiocytosis, leukemia, chronic granulomatous disease, or HIV. Other rare findings included organizing thromboemboli, chronic alveolar hemorrhage, organizing pneumonia, diffuse necrosis and fibrosis, congestion, chronic small airways disease, and respiratory bronchiolitis.

TABLE 1

Tissue Distribution of Viral Cytopathic Features by Phase of Disease

Tissue	Prodrome	Early	Established	Late	Post
Lung	MGC	WFC	MGC/WFC	MGC/WFC	WFC
Trachea		WFC/MGC	WFC
Thymus	MLC	MLC/WFC	MGC	WFC
Appendix	WFC/MGC		MGC	MGC
Tonsil	WFC/MGC/MLC		MGC
Oral mucosa	MGC	WFC
Lymph node	WFC/MGC	WFC	MGC	MGC
Brain					MGC/inclusions
Pituitary					MGC
Spleen		MGC	MGC	MGC
Intestine	WFC	MGC	MGC
Liver		WFC	MGC
Adrenal		MGC		WFC
Kidney				MGC

MGC, multinucleated giant cell; MLC, multinucleated lymphoid cell; WFC, Warthin-Finkeldey cell.

FIGURE 2

Microscopic images of lung and thymus. A, Lung from a 6-year-old boy with chronic granulomatous disease who died of measles. Warthin-Finkeldey cells (WFCs) are evident in the alveolar space (patient 75 from 1976, H&E, ×1,000). B, Diffuse alveolar damage with hyaline membranes and WFCs (patient 75, H&E, ×400). C, A WFC in the thymus of an 11-year-old girl who died of measles (patient 56 from 1962, H&E, ×1,000). D, Multinucleated lymphoid-like cell in thymus (patient 56, H&E, ×1,000).

WFCs in thymus tended to be localized within Hassall corpuscles FIGURE 2C (Supplemental Figure 4). There were also nonlymphoid MGCs and numerous MLCs, which had small round nuclei, scant cytoplasm, and no inclusions FIGURE 2D. Thymuses were otherwise histologically unremarkable, except for a few with scattered eosinophils. MGCs were seen in lymph nodes in germinal centers or in interfollicular areas. The MGCs sometimes had Langerhans-type nuclei. WFCs were occasionally seen in lymph node germinal centers, including in a lymph node from a patient who had been recently vaccinated for measles (Supplemental Figure 5). In some specimens, cells with single atypical nuclei were observed. Other findings included interfollicular hyperplasia, sinus histiocytosis (sometimes extensive), follicular hyperplasia, or hemorrhage. Most appendectomy specimens from patients with acute or chronic appendicitis showed WFCs or MGCs in germinal centers FIGURE 3A and FIGURE 3B or scattered in the lamina propria. Other findings included ulcers or lymphoid hyperplasia. Tonsil specimens showed WFCs or MGCs in the epithelium FIGURE 3C or MGCs in lymphoid tissue FIGURE 3D (Supplemental Figure 6). Tonsils of patients with Koplik spots showed WFCs in the buccal mucosa and MGCs in both epithelium and lymphoid tissue.

FIGURE 3

Microscopic images of appendix and tonsils. A, Appendix of an 8-year-old girl with appendicitis showing multinucleated giant cells (MGCs) in a germinal center. Two days after surgery for appendicitis, she developed fever and lymphadenopathy and, the next day, morbilliform rash, Koplik spots, and conjunctivitis (patient 20 from 1946, H&E, ×200). B, Warthin-Finkeldey cells in a germinal center in the appendix (patient 20, H&E, ×400). C, Tonsillectomy with MGCs in the epithelium (patient 23 from 1950s, H&E, ×200). D, Tonsillectomy with MGCs in a germinal center (patient 23, H&E, ×200).

No WFCs were seen in brain specimens, although MGCs or eosinophilic intranuclear inclusion bodies within neurons or glial cells FIGURE 4A and FIGURE 4B were seen in brain specimens from patients in the postmeasles phase. Edema was the most common finding during the early phase. Some patients with specimens showing no histologic changes had grossly apparent cerebral edema with clinical symptoms. Among specimens from patients with established measles, there were microglial activation, microglial nodules FIGURE 4C, perivascular inflammation, and cerebral edema. Sections of brain from patients with neurologic symptoms beginning 3 months to 7 years after measles infection showed gliosis with or without microglial nodules and varying degrees of perivascular lymphocytic infiltration FIGURE 4D. Review of electron micrographs taken of a brain specimen in 1991 showed intranuclear filaments in glial cells consistent with measles nucleocapsid strands (Supplemental Figure 7).

FIGURE 4

Microscopic images of brain. A, Eosinophilic ground-glass inclusion filling the nucleus, as may be seen in primary or acute postmeasles encephalitis or measles inclusion body encephalitis (patient 31 from 1957, H&E, ×600). B, Higher-power view of an intranuclear inclusion (patient 31, H&E, ×1,000). C, Microglial nodules consistent with acute viral encephalitis in a 19-year-old Army private who became comatose 5 days after the onset of measles and died 1 week later (patient 14 from 1944, H&E, ×400). D, Gliosis, activated microglia, and perivascular lymphocytic infiltration in a 12-year-old boy with lethargy, dyspraxia, and amnesia beginning 3 months after measles, which progressed to confusion, aphasia, ataxia, and death at 5 months, typical of subacute sclerosing panencephalitis (patient 74 from 1968, H&E, ×200).

Eyes that had been enucleated because of complications of measles showed no WFCs or MGCs. Findings included corneal ulceration, scarring, and perforation and endophthalmitis, often with secondary bacterial infection.

The histologic findings in other tissues are summarized in TABLE 2. No WFCs or MGCs were seen in spinal cord, upper gastrointestinal tract, pancreas, thyroid, parathyroid, heart, skin, ovary, uterus, bladder, breast, prostate, testis, epididymis, eye, or soft tissue specimens. Skin specimens showed varying degrees of ulceration and chronic inflammation. Other skin specimens included patients with Steven-Johnson syndrome and vaccine injection site reaction (Supplemental Figures 8 and 9). RNAScope amplification and in situ hybridization assay failed to detect housekeeping gene (ubiquitin) gene signals in 15 of 16 specimens tested, indicating that RNA was too degraded. Electron microscopy performed on an autopsy tissue block specimen of lung showed possible aggregates of intranuclear fibrous filaments and 200-nm cell surface buds consistent with budding virions. No definite nucleocapsid strands were identified.

TABLE 2

Histologic Findings in Other Tissues Not Described in the Text

Tissue	Histologic Findings
Adrenal	Lipid depletion, neutrophils, cortical necrosis
Bladder	Mucosal erosion
Bone marrow	Normal
Breast	Periductal chronic inflammation
Esophagus	Esophagitis
Heart	Chronic interstitial inflammation
Kidney	Congestion, mild chronic inflammation
Liver	Micro- and macrosteatosis, glycogenated nuclei, apoptosis, inflammation, Kupffer cell hyperplasia, sinusoidal dilatation, congestion, necrosis
Ovary	Normal
Pancreas	Degenerated cells, chronic inflammation
Parathyroid	Normal
Prostate	Chronic inflammation
Skin	Ulceration, chronic inflammation, Steven-Johnson syndrome, vaccine site reaction (Supplemental Figures 8 and 9)
Soft tissue graft	Foreign body–type reaction
Spleen	Hemorrhage, congestion
Testis/epididymis	Chronic inflammation
Thyroid	Incidental follicular module
Uterus	Normal

Causes of Death and Comorbidities

Among patients for whom the cause of death was determined, 64% died of respiratory-related disease, and 22% died of central nervous system (CNS) disease. Among the patients who died of respiratory disease, most had pneumonia, especially bacterial pneumonia. Acute encephalitis, meningitis, meningoencephalitis, cerebral hemorrhage, or subacute sclerosing panencephalitis (SSPE) were present among the patients who died of CNS disease. Other diseases among deceased patients included HIV infection, polio, hypogammaglobulinemia, frequent respiratory infections, infection with both Escherichia coli 0111 and cytomegalovirus, pulmonary Aspergillus infection, otitis media, varicella, rubella, tuberculosis, noma, ascariasis, small airways disease, asthma, smoking-related diffuse lung disease, malnutrition, failure to thrive, leukemia, congenital heart disease, and Langerhans cell histiocytosis. Patients who were not deceased also had chronic tonsillitis, ascariasis, pneumococcal pneumonia, congenital hydrocephalus with renal disease, and malnutrition. One patient with HIV infection had no rash but apparently acquired measles during an outbreak among unvaccinated children.¹² One girl with abdominal muscle weakness from polio was unable to cough and died of staphylococcal pneumonia. Further details of underlying diseases are described in Supplemental Table 2.

DISCUSSION

WFCs, defined as multinucleated cells with eosinophilic nuclear inclusions, are pathognomonic of measles.¹⁰ Although MGCs may be present in tissues from patients with a variety of inflammatory reactions with both viral and nonviral etiologies, in the context of measles, we interpret MGCs without inclusions to be virally infected cells. Recognition by pathologists of WFCs, MGCs, and MLCs in routine specimens, such as lymph node, appendectomy, and tonsillectomy specimens, may alert clinicians to unsuspected cases of measles, perhaps allowing for earlier diagnosis and patient isolation.

Measles virus is believed to first infect alveolar macrophages or dendritic cells, which transmit the virus to bronchus-associated lymphoid tissue and then to trachea-bronchial lymph nodes.^9,13-15 Viremia occurs, disseminating virus throughout the lymphoid system, followed by infection of epithelial cells of the airway. This model is compatible with the anatomic locations of the WFCs and MGCs that we observed TABLE 1. In lymph nodes, WFCs and MGCs were in germinal centers in the prodromal and early phases, as previously reported,¹⁶ whereas WFCs and MGCs were in both germinal centers and interfollicular areas in established and late phases. WFCs and MGCs were in germinal centers and lamina propria in appendix tissue from patients in prodromal, established, and late phases of infection and also in the epithelium and lymphoid tissue of tonsils from patients in the prodromal and established phases, similar to previously reported findings.^10,17-19 In thymus, innumerable MLCs appeared in prodromal and early phases, whereas only epithelial WFCs and MGCs were present in established and late phases.

Among patients who died with measles, respiratory disease was the most common cause of death. As has been previously documented,²⁰ measles infection causes direct injury to the lung, resulting in the diffuse alveolar damage seen in some of the patients in this study. Measles also likely causes increased susceptibility to bacterial lung infection. Although the trend was not statistically significant, bacterial infections became less prevalent in our patients with measles between 1919 and 1970 as antibiotics became more available and effective; there were no patients with bacterial infections in the 1970s and 1980s (Supplemental Figure 10). The prevalence of bacterial infections increased again in the 1990s, corresponding to the cohort of patients with HIV infection. One patient was a 23-year-old soldier whose fatal measles infection in 1919 was complicated by otitis media extending into brain. His case was like that of victims of a US Army-wide parallel measles and streptococcal outbreak in 1917-1918, which resulted in a case fatality rate higher than that of the later 1918 influenza epidemic.^21,22 Even then, it was recognized that viral and bacterial interactions increased morbidity. It is now known that children have increased rates of contracting other infections for up to 5 years after having had measles, and recent studies suggest that measles infection causes an immune amnesia to nonmeasles infections.^9,23,24

Clinicians and pathologists caring for immigrant and internationally adopted children should be alert to the possibility of measles-related CNS disease.²⁵ Measles-induced encephalitis has been categorized into four types: primary measles encephalitis, acute postmeasles encephalitis, measles inclusion body encephalitis, and SSPE.²⁶ In primary measles encephalitis, the brain becomes infected during the rash phase in approximately 1 in 1,000 to 3 in 1,000 patients. There may have been measles outbreaks with a higher incidence of primary measles encephalitis: contributors reported that measles in San Antonio in January and February 1961 was associated with an unusually high number of patients with encephalitis and meningitis. One family lost two young children from this complication within 2 days. The measles virus has been shown to localize within endothelial cells in acute measles encephalitis.²⁷ Disruption of endothelial cell function in the brain may account for the cerebral edema we observed.

Acute postmeasles encephalitis is thought to be an immune-mediated demyelinating reaction occurring in approximately 1 in 1,000 patients 2 to 30 days after the onset of measles, which overlaps with primary measles encephalitis.^26,28-31 In fact, both primary measles encephalitis and acute postmeasles encephalitis may occur simultaneously. Approximately 1 in 1,000,000 to 2 in 1,000,000 children are affected following live measles vaccination.^31,32

Measles inclusion body encephalitis (also called acute progressive encephalitis) is a rare condition that typically occurs within 1 year of measles infection in immunodeficient children, in whom there is persistent viral infection in the brain.^28,33

SSPE has an incidence of 1 in 25,000 patients with measles infections overall but occurs in up to 1 in 5,500 infants with measles.^25,26,34 Failure to clear viral infection of neurons and glial cells results in a progressive degenerative disease usually beginning 5 to 15 years after acute measles. Atrophic lesions first appear in the gray matter and progress into periventricular white matter and eventually into the brainstem, resulting in coma and death. Among our patients who had neurologic symptoms 3 months to 7 years after measles infection, the presence of eosinophilic intranuclear inclusion bodies within neurons and glial cells provides evidence of persistent viral infection, whereas gliosis, glial nodules, and perivascular lymphocytic infiltration demonstrate continued inflammatory response.

Measles is the leading cause of blindness among children in low-income countries, perhaps with vitamin A deficiency as a cofactor.^9,35 Most cases of measles blindness result from xerophthalmia, corneal ulceration, keratomalacia, and subsequent corneal scarring or phthisis bulbi. The eye specimens we evaluated were from patients who underwent enucleation because of pain, blindness, or bacterial infection. The period of time between the onset of measles and enucleation ranged from 1 week to nearly 50 years. Five (71%) of the patients were from low-income countries. Patients from the United States included a woman born in 1908 who had measles as a child and a 22-month-old with acute measles. Although measles blindness may also result from retina or optic nerve disease in association with SSPE, none of our specimens showed any primary retinal disease.

A limitation of our study was the inability to detect adequate measles virus messenger RNA in archival tissue. Future studies may include immunohistochemistry to identify infected cell types. Electron microscopy shows measles virus–infected cells have masses of helical nucleocapsid strands in the cytoplasm, intranuclear tubular structures, and budding viral particles on the surface³⁶; however, electron microscopy is not optimal for identifying virus in formalin-fixed, paraffin-embedded tissue.

Our repository includes specimens from cases of veterinary morbillivirus infections, including cetacean and phocine morbilliviruses and canine distemper virus (Supplemental Figure 11).^37-40 Cooperative studies by veterinary and human pathologists in our institution have produced data that contribute to the understanding of these infections in all species affected. Our institution has a heritage of providing support to military service members with their distinct risk factors. Although measles is an unlikely bioweapon, it has been the subject of biodefense investigations in several nations.¹³

CONCLUSIONS

Measles may result in profound morbidity and mortality, both acutely and for many years after initial infection. Respiratory disease is the most common cause of acute morbidity, whereas neurologic disease is the most common cause of acute and chronic morbidity. Bacterial infection is a significant cofactor in adverse outcomes, especially in immunocompromised patients. Pathologists may play a role in the diagnosis of measles; to this end, this study provides educational digital slides with clinical data (supplemental data).

Disclaimer: The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Army, Navy, or Air Force; Department of Defense; or US government.

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Acknowledgments

We thank Anula Bhusry, Philip Branton, MD, Barbara A. Crothers, DO, John F. Fetsch, MD, James R. Hallman, MD, Robert V. Jones, MD, and Anupamjit K. Mehrotra, MD, for their contributions to this study. We also thank Ellen Lazarus, MD, ELS, for medical editing assistance.