Orthopoxvirus Testing Challenges for Persons in Populations at Low Risk or Without Known Epidemiologic Link to Monkeypox — United States, 2022

Description of Patients

Patient A, a healthy pregnant woman (estimated 37 weeks’ gestation) was evaluated for labor and was noted to have a pruritic erythematous rash on her arms, abdomen, upper back, calves, and shins. Her lesions, not typical for monkeypox, had irregular borders, and were different sizes and in different stages of development (i.e., tan papules, crusted papules, pustules, and hyperpigmented macules) in the same anatomic locations, with reported onset 5 weeks earlier. No genital lesions were present. She did not report typical prodromal signs or symptoms of monkeypox (e.g., body aches, lymphadenopathy, fever, or chills). A household member was reported to have a similar rash, with onset 4 days before that in patient A; that person’s rash resolved within 1 week, and no testing was performed; no epidemiologic link to a person with monkeypox was identified. Patient A had no interstate or international travel during the 3 weeks preceding rash onset. She reported varicella infection and receipt of smallpox vaccination as a child. Tests for varicella-zoster virus, syphilis, herpes simplex virus, cryptococcosis, and histoplasmosis were performed, all with negative results. A swab from a pustular forearm lesion, obtained 53 days after rash onset yielded a positive NVO test result (Table). Two days after receiving the result, the woman had an uncomplicated vaginal delivery of a healthy neonate. The state health department and CDC clinicians recommended several measures until lesions resolved: 1) initiation of monkeypox infection-control precautions^¶ in the hospital, 2) precautions to prevent skin-to-skin contact between mother and infant,** 3) designation of another household member as the primary caregiver, 4) delay of breastfeeding, and 5) disposal of breast milk. Because of concern for congenital or perinatal transmission, vaccinia immune globulin intravenous (VIGIV) was administered to the neonate under a single patient emergency Investigational New Drug application. Further testing with a Clade II (i.e., West African) MPXV–specific real-time PCR LDT was inconclusive. Because of the discordant results, serum from patient A obtained on day 42 after rash onset was sent to CDC for serologic analysis; no antiorthopoxvirus antibodies were detected, arguing against orthopoxvirus infection (9). The recommendations restricting contact with the baby and for delaying breastfeeding were discontinued after rash resolution when the infant was aged 21 days (Figure). The patient’s skin lesions were most likely attributable to bed bugs, which was a diagnosis that the clinical care team considered initially but set aside upon receipt of the positive NVO result.

Patient B is an elementary school–aged, previously healthy child (Table). The child developed influenza-like symptoms followed 2 days later by raised lesions on the face. The next day, lesions had spread to the trunk, back, and arms. The lesions were initially papulopustular, and over the course of 2 days became ulcerated and crusted. No epidemiologic link to a person with monkeypox was identified. A swab of a facial lesion tested positive by an orthopoxvirus generic LDT. Treatment with tecovirimat was started because the child had periorbital lesions and because of concern for potential ocular autoinoculation and development of sight-threatening disease. The child lived with four other persons and had engaged in a contact sport when the rash was present. The child isolated at home, and all family members received PEP with JYNNEOS vaccine; PEP for teammates was held pending reextraction and retesting of the original specimen (Figure). The subsequent result was negative, and the child was released from isolation. Enterovirus PCR testing was positive, suggesting a diagnosis of hand, foot, and mouth disease.

Patient C is an infant who visited the United States with both parents for approximately 1 month and subsequently traveled to another country with four other families for vacation. During that trip, the infant experienced diarrhea followed by lymphadenopathy, and 2 days later, after returning to the United States, developed fever and a rash (Table). The rash was described as maculopapular and vesicular, and started on the arms and legs progressing to the earlobe, chest, scalp, and lower abdomen; the rash scabbed over 2 weeks later. One abdominal lesion tested positive by NVO and an orthopoxvirus generic LDT; two other lesions tested negative. The infant was treated with oral tecovirimat. No epidemiologic link to a person with monkeypox was identified. Over a 15-day period starting on the second day of the vacation, five of 11 children (including patient C) and four of 14 adults from the families who vacationed with the infant experienced rashes that varied in appearance. Among some of the children, the rash looked like insect bites and not consistent with monkeypox; among others, the rash was vesicular or pustular involving the arms, legs, feet, fingers, or face, and eventually scabbing over. Results of NVO testing of lesions on four children and four adults were negative or inconclusive. A multijurisdictional investigation was launched to determine potential exposures and administer PEP to all family members. Twelve adults and seven children (aged 0–14 years) received PEP with JYNNEOS. Because of the ongoing investigation, multiple families changed travel plans, and patient C’s family postponed travel back to their country of residence for approximately 4 weeks. Serum from two adults and four children (including patient C) obtained 3–31 days after rash onset did not detect the presence of antiorthopoxvirus antibodies (Figure).

Discussion

Evaluation of these three patients for monkeypox highlights the need for caution in interpreting single laboratory test findings in patients with a low pretest probability of infection; this includes lack of an epidemiologic link, non-MSM populations (e.g., women and children, who currently account for <2% of confirmed monkeypox cases), and signs, symptoms, or rash progression inconsistent with monkeypox. This approach is similar to the caution recommended in evaluating other laboratory tests when pretest probability is low (e.g., D-dimer results for a deep vein thrombosis or serology for Lyme disease)^†† (10). Multiple clinical features in each of these three patients were inconsistent with monkeypox, including an atypical rash that was inconsistent with the characteristic progression of monkeypox lesions, as well as the absence of an epidemiologic link to a known case of monkeypox. The Ct values of all initial positive test results were high (≥34) indicating a low level of viral DNA. Cautious interpretation of test results is warranted when the pretest probability of monkeypox is low. As monkeypox testing has expanded, CDC recommends that laboratory professionals verify positive diagnostic results (8) for Orthopoxvirus or MPXV DNA in specimens with high Ct values, especially from persons who do not meet epidemiologic risk criteria for monkeypox or for whom lesions do not progress as expected. Molecular tests (e.g., real-time PCR tests) are highly specific and sensitive; however, when epidemiologic criteria are absent or unknown and the Ct value is high (generally ≥34), CDC recommends reextraction and retesting of the specimen.

Monkeypox currently occurs predominantly among MSM, although infection can occur in any person after close physical contact with persons with monkeypox or items that have been in contact with lesions, such as clothing or bedding. Because the positive predictive value in populations with low disease incidence is lower than that in populations with a higher disease incidence, laboratory results in persons with low pretest probability of infection should be carefully examined and reviewed, and other plausible diagnoses (e.g., hand, foot, and mouth disease; varicella; molluscum contagiosum) should be considered. The clinical course of illness should be reviewed, including documenting the lesions with photographs. CDC can be consulted for atypical or questionable cases and can perform additional viral-specific and clade-specific PCR testing and antiorthopoxvirus serology.

CDC Monkeypox Emergency Response Team

Ramona Bhatia, CDC; Anne Kimball, CDC; Brett Petersen, CDC; Yon Yu, CDC; Kevin Chatham-Stephens, CDC; Kia Padgett, CDC; Maureen J. Miller, CDC; Isaac Zulu, CDC; William C. Carson, CDC; Sapna Bamrah Morris, CDC; Caroline Schrodt, CDC; Amy Beeson, CDC; David Kuhar, CDC; Zeshan Chisty, CDC