Accurate diagnosis of mpox is imperative so that treatment can begin as fast as possible, write experts in the SA Medical Journal, in a case study of a patient who was initially misdiagnosed, and who may have been the first patient in SA with no travel history or contact with travellers and more than a year after no cases had been detected locally.
The man (35), with no previous medical or surgical history, no allergies, and no travel history outside South Africa for two to three weeks before the onset of illness, presented to a GP in the Eastern Cape in May 2024 with flu-like symptoms including fever, sore throat, rhinitis, fatigue and night sweats.
Self-described as homosexual, the patient was treated symptomatically and the prodrome resolved within a week of its onset
He reported having only one sexual partner for more than a year, but was uncertain of his partner’s fidelity. Both practise penetrative and anal receptive sexual intercourse, with no use of any sexual paraphernalia.
He had not participated in group sex, and all of his sexual partners had been South African, though it is unknown if they had non-South African sexual contacts before their relationship with him.
A week after the onset of illness, he had noticed lesions on the dorsal aspect of both hands. The lesions were painless and non-pruritic, and at this stage, the patient returned to Johannesburg.
Within two days, he’d developed rigors and watery diarrhoea – lasting for three days, but which resolved without treatment. He also noted that lesions with the same appearance as those on his hands were developing on his genital and perianal area, with sparing of the glans penis.
He consulted a local GO and was treated with antihistamines and oral corticosteroids as a possible hypersensitivity reaction with an atypical distribution. Two days later he went to the emergency department at a private hospital with extensive, large umbilicated pustules that were also indurated. These lesions were on his head, neck and trunk, and with fewer lesions on his extremities.
He was diagnosed with molluscum contagiosum and discharged with a referral letter to see a dermatologist. The next day, failing to get an early appointment with the dermatologist, he returned to the hospital and was admitted to an isolation ward.
On examination, it was reported that he had basal crackles bilaterally, but was not in respiratory distress, and his room air oxygen saturation was 96%. He had significant generalised lymphadenopathy, including in the cervical, axillary and inguinal areas.
The lymph nodes were firm and tender, ranging in size from 2cm-3 cm in diameter.
Dermatological examination revealed extensive widespread papules and vesiculo-pustular skin lesions, some with central umbilication and necrosis on the face, scalp, trunk and limbs, with fewer lesions on the extremities.
There were of varying sizes and different stages of development, with some oozing, while others were beginning to crust. The lesions also involved the oral mucosa, the ano-genital area as well as the palms of the hands and soles of the feet.
The differential diagnosis at this stage included molluscum contagiosum, atypical and disseminated herpes simplex, a deep fungal infection of the skin and secondary syphilis. Blood samples were taken for baseline investigations, and the patient consented to HIV testing.
Immunocompromised
The specimens were HIV reactive with a viral load of 19 485 copies/mL and a CD4+ count of 371 cells/μL. A week after this HIV diagnosis, he was initiated on first-line combination antiretroviral therapy in the form of tenofovir disoproxil, lamivudine and dolutegravir.
His baseline full blood count (FBC) was normal except for a microcytic hypochromic anaemia and raised atypical or reactive lymphocytes and monocytes, with this latter finding persisting on subsequent FBCs and only normalising after three weeks and before the initiation of mpox-specific therapy.
In terms of his inflammatory markers, his C-reactive protein (CRP) was raised on admission at 128 mg/L (<5), he had a high ferritin of 1 183 ng/ml (normal range 34 – 310), an erythrocyte sedimentation rate of 125 (normal range 1 – 15) and his procalcitonin (PCT) was also elevated at 0.17 ng/ml (<0.05). His CRP remained elevated throughout admission and only reduced by >50% after three weeks and before initiation of mpox-specific antiviral therapy. His baseline renal function tests were normal except for a mildly elevated creatine, which normalised after intravenous fluids.
Liver function tests on admission revealed elevated alkaline phosphatase, gamma glutamyl transferase and protein, prompting serological screening for viral hepatitis, including hepatitis A, B and C, with the latter two also being important sexually transmitted viruses.
Hepatitis B surface antigen and hepatitis C total antibody tests were both negative. Cytomegalovirus and Epstein-Barr virus viral loads on blood were unremarkable.
Active infection with syphilis was also ruled out on serology. Blood cultures remained negative throughout his admission.
Punch biopsies of skin lesions were submitted for histological evaluation on two separate occasions. All samples showed a zone of coagulative necrosis of the epidermis with an overlying thick, inflammatory crust.
The intact epidermis showed marked hyperplasia and ballooning degeneration of keratinocytes, as well as eosinophilic hyaline globules within the cytoplasm of degenerate keratinocytes.
The latter changes were later interpreted as Guarnieri-type intracytoplasmic inclusions. These were accompanied by a conspicuous exocytosis of neutrophils with associated karyorrhexis.
In addition, there were degenerate keratinocytes exhibiting intranuclear eosinophilic inclusions as well as isolated keratinocytes showing multinucleation, suggesting herpes virus infection.
However, immuno-histochemistry for herpes simplex virus 1 and 2 and varicella zoster virus were negative. There was no histological evidence of molluscum contagiosum or deep fungal infection. The underlying superficial dermis showed a moderately dense, predominantly perivascular, inflammation consisting of a mixture of lymphocytes, histiocytes and neutrophils.
There was relative sparing of the deeper dermis. Electron microscopy was performed on this last set of lesion biopsies and demonstrated the presence of orthopoxviruses and no herpes viruses were detected.
For radiological investigations, contrast computed tomography (CT) scans of the head, chest, pelvis and abdomen were performed, revealing extensive lymphadenopathy.
Although the lower lobe of the right lung showed apical nodularity suggestive of post-primary tuberculosis (TB), mycobacterial TB screening on sputa for acid-fast bacilli was negative on two occasions, as was urinary lipoarabinomannan testing.
Importantly, peri-anal and peri-rectal oedema along with regional enhancing lymphadenopathy were also observed, suggesting a proctitis. Based on the initial histopathology report showing features suggestive of herpes simplex virus infection, the patient was initiated on intravenous acyclovir 500 mg every eight hours, which was later de-escalated to oral valacyclovir 1 g every eight hours.
However, because the skin lesions were not improving on intravenous acyclovir and were instead increasing in size and distribution, a diagnosis of mpox was considered.
The skin lesions, especially those on the face, began oozing and developing honey-coloured crusts. A third biopsy and a swab were then taken for MPXV polymerase chain reaction (PCR) testing, which yielded positive results.
The results were verified at the national reference laboratory followed by full genomic sequencing. The sequence confirmed the presence of clade IIb lineage B1.20 MPXV in the specimens.
Due to the severe and extensive nature of mpox presentation in this patient, with >100 lesions, and his immunosuppressive state as a newly diagnosed HIV-infected patient, assistance for access to tecovirimat pox antiviral treatment, which is not registered in SA, was requested from the World Health Organisation (WHO).
Access was gained for 21 authorisation for compassionate use from the SA Health Products Regulatory Authority. The drug was received, and the patient was initiated on oral tecovirimat 600 mg twice daily, and completed 14 days of therapy.
During the treatment, he had no side effects, and after three days of therapy, he was feeling subjectively better and his lesions objectively appeared to be improving. He was discharged on 31 May 2024.
Travel history
In 2022, during the peak of the ongoing multi-country mpox outbreak, SA recorded five cases of mpox, all in adult MSM males aged 28-41, with the last SA case reported in 2022. These cases had travel histories or close contact with travellers, which would be the most likely explanation for their exposure and subsequent infection.
The case reported here, however, is the first case of mpox in SA with no travel history or close contact with travellers, and more than a year after which no mpox cases had been detected locally.
This case was characterised by severe mpox infection with HIV-induced immunosuppression. The patient’s risk factors for infection are in keeping with the global mpox outbreak, i.e. MSM and <40 years of age.
The occurrence of this case, with no travel history, could mean that MPXV had either been circulating in SA undetected for a whole year (2023), ever since the first reported local cases in 2022, which is very unlikely, or there could have been a new, recent reintroduction of clade IIb MPXV into the country by a travelling infected person(s).
Unlike the previous five SA cases and the majority of the cases during the global outbreak, where lesions were mostly confined to the ano-genital and oral areas, the patient described here had an extensive disease presentation with <100 lesions covering almost every part of his body, and a protracted disease course spanning more than seven weeks.
Reasons for this severe presentation include concomitant immuno-suppression due to an undiagnosed and untreated HIV infection at the time, the administration of corticosteroids during the earlier stages of the disease when the patient was misdiagnosed and treated for an allergic skin reaction, and mpox immune reconstitution inflammatory syndrome after initiation of HIV antiretroviral therapy soon after admission and before the mpox diagnosis was confirmed.
During the ongoing global mpox outbreak, severe and/or prolonged disease was reported in patients with underlying immune deficiencies, including uncontrolled HIV and CD4 counts <200 cells/μL.
The issue of misdiagnosis and delayed diagnosis in this patient is important. It took three weeks from when the first mpox lesions appeared on his hands to when mpox was considered and confirmed on PCR.
The patient had erroneously been diagnosed with allergies, molluscum contagiosum and then herpes simplex virus infection. Prolonging the time to final diagnosis may have significant implications for both the patient and from a public health perspective.
For the patient, delayed diagnosis may result in severe disease with complications, and from a public health perspective, delay in diagnosis may result in further transmission chains occurring. Based on the clinical presentation of the rash, the differential diagnosis in these cases is broad, and includes chickenpox (caused by varicella zoster virus), molluscum contagiosum, deep fungal infection, syphilis, bacterial skin infection, scabies and allergies.
Ano-genital lesions may be associated with proctitis (rectal pain, tenesmus, bleeding and discharge), and ano-rectal local oedema, which was demonstrated on CT scan in this patient.
In contrast to chickenpox, the mpox rash is usually non-pruritic, and lesions are typically significantly larger, pustular or umbilicated. Although the mpox lesions are supposed to present in the same stage of evolution, this was not the case in this patient, where the lesions were at different stages of development.
Additionally, lymphadenopathy is more likely to occur with mpox than with chickenpox or herpes simplex.
The presence of epidemiological risk factors, e.g, MSM or sex workers, and regions of the body affected, e.g, ano-genital, as well as accompanying symptoms such as tender regional lymphadenopathy and proctitis, should create a high index of suspicion for mpox and help to narrow the differential.
The diagnostic dilemma surrounding mpox and severe infection in an immunocompromised individual is highlighted in this patient.
Study details
Severe mpox in an immunocompromised patient, SA 2024
E Vardas, M Naidoo, Chopdat et al.
Published in SA Medical Journal in October 2024
A previously healthy 35-year-old male belonging to the men who have sex with men (MSM) community, practising both penetrative and receptive anal sex for the past 10 years, and with no travel history outside South Africa, presented initially with a prodrome of fever, sore throat, night sweats, myalgia and fatigue. A week after the onset of these nonspecific symptoms, the patient noted painless, non-pruritic skin lesions measuring 2 mm-15 mm in diameter on the dorsum of his hands. Three days later he developed rigors, watery diarrhoea and similar lesions on his genital and perianal areas. A week later, the patient presented to the emergency department with extensive lesions encompassing almost his entire body. He was admitted with suspected mpox infection. Imaging showed extensive lymphadenopathy, and the diagnosis was confirmed by mpox polymerase chain reaction testing. During the admission, he was also newly diagnosed with HIV infection. Treatment with tecovirimat was initiated, and the patient recovered, albeit with significant depigmentation and scarring.
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