Postinfectious immunologic syndromes

The high prevalence of “long COVID” and our inability to fully understand its pathophysiology, develop successful treatment paradigms, or even delineate reliable clinical biomarkers^1,2 prompted me to review our understanding and management of other postinfection syndromes. Some, like post–Lyme disease syndrome and postinfectious mononucleosis, have overlapping features with long COVID and chronic fatigue syndrome (myalgic encephalomyelitis/chronic fatigue). The primary cellular target(s) remains elusive, although the central nervous system seems to be an active participant. Active ongoing infection seems to be an unlikely explanation. Long COVID joins a number of other postinfectious syndromes that have been delineated over the past 400 years. Others are associated with readily demonstrated objective and sometimes unique clinical signs.

Reviewing the historical evolution of other syndromes reveals a common thread of initial clinical description by astute clinicians followed by a significant delay until the relationship with a triggering infective agent was identified. Then there was further delay until some understanding of the host immune response in the development of the postinfectious syndrome was elaborated. As histologic, immunologic, and molecular technologies have improved, some of the missing pieces of these pathogenic puzzles have been filled in, but a full pathophysiologic understanding of many of these postinfectious syndromes remains incomplete. An overarching paradigm has evolved that the immune response to specific infectious vectors somehow spills over to include an “autoimmune” response involving selected host tissues. The clinical phenotype seems to depend on the specific infecting vector and the host’s immune status and genetic background. The immune pathogenesis dictates the pattern of organ involvement, histopathology, and clinical course.

In the 1600s, the clinical pattern of acute “rheumatic arthritis” was distinguished from gout. The association with carditis was not appreciated for over 100 years, and it was not until the early 20th century that the relationship between acute rheumatic fever (ARF) syndrome and prior infection would be described in Coburn and Pauli’s landmark publication.³ A different syndrome, urethritis followed by arthritis, was described as early as the 16th century, and postdysentery arthritis⁴ was described a century later. But it was not until the early 20th century that several European physicians independently more fully described the postinfectious syndrome of asymmetric arthritis and enthesitis, noninfectious urethritis, conjunctivitis, and several unique skin manifestations that is now known as reactive arthritis.^* The bacterial triggers associated with these 2 syndromes are different: ARF is strongly linked with streptococci (primarily group A mucosal infections), and reactive arthritis is associated with a number of triggers, including genitourinary (Chlamydia trachomatis) and intestinal (eg, Shigella, Yersinia, Campylobacter, Clostridioides difficile, and Salmonella) infections.

The exact mechanism by which these infections trigger their postinfectious inflammatory reactions is not known. Both antigenic mimicry and neoantigen generation have been proposed to explain ARF.⁵ The proposed pathophysiology driving the expression of reactive arthritis includes the persistence of bacterial antigens (presumably tropic to specific joint, eye, skin, and tendon locations) that are then reacted to by those individuals carrying an immune genetic background that favors an ongoing T-cell–driven response⁶; notably, not all patients with reactive arthritis carry the implicated HLA-B27 haplotype.

Streptococcus species seem to trigger more and varied postinfectious syndromes than other bacteria, in addition to ARF. The clinical expression of these syndromes may be influenced by the Streptococcus species involved (with different surface antigens) and by the location and persistence of the primary infection. It is striking that although these syndromes can all be triggered by streptococci, the immunopathology is quite different between ARF (mixed humoral and cell-mediated cytotoxicity), post-streptococcal glomerulonephritis (immune complex), guttate psoriasis (possibly streptococcal superantigen), and erythema nodosa (type 4 hypersensitivity).^7–9

A number of postinfectious inflammatory skin reactions have been described, several of which have been strongly associated with respiratory infections, especially with Mycoplasma pneumoniae. The diagnostic terminology and histopathologic distinction can be challenging, and the clinical features of these reactions can overlap, with the relative severity of tissue damage also playing a role in the final diagnosis. Erythema multiforme is an acute, cell-mediated, antikeratinocyte mucocutaneous reaction characterized by raised, predominantly acrally located target lesions that may spread to the trunk and occasionally involve the mucosal surfaces, although a subset of patients have significant mucosal involvement.¹⁰ Common triggers of erythema multiforme include herpes simplex and M pneumoniae infections. The clinical outcome is generally favorable. Recognition of erythema multiforme can provide a clue to the presence of an undiagnosed infection, prompting diagnostic testing and appropriate anti-infective therapy.

Reactive infectious mucocutaneous eruption (RIME), also commonly triggered by M pneumoniae, is pictured and discussed in this issue of the Journal.¹¹ It presents with lesions similar to those of erythema multiforme, but in its most common presentation, it is the mirror image of erythema multiforme, with striking mucosal involvement and sparser truncal and acral lesions. Recognition again should prompt evaluation for a persisting respiratory infection. Its appearance and pathophysiology are different from erythema multiforme. RIME is mediated by immune complex deposition and complement activation. The sparse truncal involvement also helps distinguish RIME from allergic drug reactions.^12,13 When RIME causes severe mucosal damage, its appearance may suggest Stevens-Johnson syndrome, which has a more dire prognosis. Initially associated with M pneumoniae and termed M pneumoniae–induced rash and mucositis,¹³ RIME has been reported as following shortly after other bacterial and viral respiratory infections.¹²

The myriad of severe autoimmune syndromes associated with the use of the newer checkpoint inhibitors in the treatment of malignancies¹⁴ is another dramatic reminder that activation of the immune system can be associated with many off-target manifestations.

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