How the United States syphilis epidemic may portend a resurgence of an unusual hematologic condition: The connection between syphilis and paroxysmal cold hemoglobinuria
Authors: Jeremy W. Jacobs, Garrett S. Booth, Jennifer S. Woo, Brian D. Adkins, Laura D. Stephens
Journal: American Journal of Hematology (2023)

The connection between syphilis and paroxysmal cold hemoglobinuria. A recent World Report in The Lancet discussed the dramatic increase in syphilis cases in the USA, rising to the highest total in seven decades.1 This has been partially augmented by a shortage in benzathine penicillin G (benzathine benzylpenicillin), highlighted in an October 2023 letter from the National Coalition of STD Directors and 38 other public health groups to members of the White House Drug Shortage Task Force.2 While alternative therapies are available, these regimens are more cumbersome. Further, benzathine benzylpenicillin—a long-acting form of penicillin manufactured exclusively by Pfizer—is the preferred therapy for primary and secondary syphilis in adults, infants, and children, and the only therapy approved for pregnant patients.1 While the limited access to this crucial drug is undoubtedly a contributing factor, syphilis rates were increasing prior to the antimicrobial supply constraints.3 The increasing prevalence of syphilis, and the potential for shortages of optimal therapy, may culminate in a public health emergency declaration.1 Moreover, the increase in infected individuals, particularly if untreated, may lead to a rise in the incidence of paroxysmal cold hemoglobinuria (PCH), a lesser-known hematologic consequence of syphilis. PCH, one of the rarest forms of autoimmune hemolytic anemia in adults, is characterized by an unusual "biphasic" autoantibody that binds to red blood cells (RBCs) in cold temperatures or cooler areas of the body. Upon rewarming, a complex cascade involving the complement system ultimately induces cellular destruction. The resulting anemia may be profound and life-threatening. Historically, PCH was almost invariably observed as a chronic or relapsing condition in patients with congenital or tertiary syphilis.4-6 Following the advent of penicillin and the subsequent reduction in syphilis, contemporary PCH primarily occurs in children following upper respiratory infections. Pediatric cases tend to be self-limited, though historic reports of syphilis-associated PCH describe a relapsing remitting course, and it is unclear if their modern equivalent will take on a chronic form after penicillin therapy. Few reported cases of PCH in adults without syphilis have been reported, and have been suggested to occur in the setting of an underlying hematopoietic neoplasm.5 However, with the mounting cases of potentially untreated syphilis, this often-overlooked disorder may reemerge. Thus, healthcare professionals, particularly those caring for adult patients, must be vigilant for this peculiar condition. This potential resurgence, and diagnostic conundrum, is aptly illustrated by a recently encountered case. A 46-year-old female presented with a chief complaint of fatigue and dyspnea on exertion. She had been diagnosed with influenza A infection 3 months prior and received oseltamivir, but otherwise denied recent infection or illness and had no significant past medical history. On exam, she was febrile (38.3°C), tachycardic (heart rate 104 beats/min), tachypneic (24 breathes/min), with borderline hypoxemia (92% oxygen saturation). Chest x-ray demonstrated no evidence of infiltrate, effusion, or lymphadenopathy. Laboratory evaluation revealed new onset anemia (hemoglobin 6.5 g/dL, reference: 11.9–15.1 g/dL, 3 weeks prior: 12.1 g/dL), with normal white blood cell and platelet counts. Further studies demonstrated evidence of hemolysis (lactate dehydrogenase: 870 U/L, reference: 124–235 U/L; haptoglobin: <8 mg/dL, reference: 30–240 mg/dL; total bilirubin: 3.3 mg/dL, reference: <1.2 mg/dL). Immunohematologic evaluation showed ABO type A with a negative antibody detection test. Direct antiglobulin testing (DAT) demonstrated complement (C3) (reactivity: 3+) but not immunoglobulin G (IgG) (reactivity: 0) bound to her RBCs. An elution was non-reactive when tested against three reagent screening RBCs. She was subsequently diagnosed with cold agglutinin syndrome (CAS), and extensive evaluation for underlying etiologies was performed. Testing for infectious agents (Mycoplasma pneumoniae, Epstein–Barr virus, HIV, hepatitis B, hepatitis C, SARS-CoV-2) and hematolymphoid neoplasms (serum protein electrophoresis, urine protein electrophoresis, peripheral blood flow cytometry) was unremarkable. Ultimately, she was diagnosed with idiopathic CAS, though the potential for her remote influenza infection as a potential etiology could not be excluded. Two units of compatible RBCs were administered acutely given the patient's symptoms, with a transient rise in hemoglobin. Two days later, she required an additional unit of RBCs due to continued hemolysis, and a four-week course of rituximab (375 mg/m2 once every 7 days) was initiated. She continued to require RBC transfusion every 2–3 days over the next 3 weeks. Given the patient's continued hemolysis with no response to rituximab and absence of identifiable underlying etiology, second-line therapy was considered, and the transfusion medicine service was consulted for additional immunohematologic testing recommendations. A cold agglutinin titer was performed at 4°C, with cold agglutinins detected at a titer of 32. A 4°C auto-control revealed 1+ agglutination. A thermal amplitude test demonstrated a narrow thermal amplitude, with no agglutination or hemolysis detected above 20°C. With this constellation of findings, the diagnosis of CAS was questioned. Further workup was performed, including a Donath-Landsteiner test, which demonstrated robust hemolysis in the sample that was incubated at 4°C and then 37°C, but no hemolysis in the samples incubated only at 4 or 37°C, indicative of a positive result. A diagnosis of PCH was made, and evaluation for Treponema pallidum was recommended, which was ultimately positive (reactive rapid plasma reagin and T. pallidum particle agglutination tests). Given the unknown duration of infection, the patient was initiated on a 3-week course of benzathine penicillin G (2.4 million units each week). Following this treatment, the hemolysis began to resolve, and she became transfusion-independent, though she remained anemic (hemoglobin 10.8 g/dL) on last evaluation prior to being lost to follow-up. PCH diagnosis requires a high degree of suspicion and specialized laboratory testing. Without specific evaluation for PCH, the condition may be misdiagnosed as CAS, as highlighted in this case. Collaboration among hematologists, transfusion medicine physicians, laboratory professionals, and other healthcare practitioners is paramount to ensure timely diagnosis and optimal therapy. Furthermore, confirmation, or suspicion, of PCH should invoke the possibility of undiagnosed syphilis, and evaluation for T. pallidum should be undertaken, as appropriate therapy may induce remission of hemolysis and mitigate the need for transfusion support. Ultimately, given the increasing syphilis rates, the epidemiology of PCH may revert to that of the early-mid 20th century, and should be considered in the differential for all patients presenting with signs of hemolytic anemia in the ensuing years. The authors declare no conflicts of interest. Data not available as no new data were generated.