Exuberant molluscum contagiosum as a manifestation of the immune reconstitution inflammatory syndrome
1. Hospital de Curry Cabral, Dermatology Department, Lisbon, Portugal. firstname.lastname@example.org
2. Hospital de Curry Cabral, Infectious Diseases Department, Lisbon, Portugal
Immune reconstitution inflammatory syndrome (IRIS) is a recently described entity in which severely immunodepressed HIV patients, after being started on HAART, develop inflammatory reactions to several pathogens. We present a patient who developed extensive Molluscum Contagiosum (MC) lesions shortly after being started on HAART. With the progression of immunoreconstitution, the lesions healed spontaneously. Molluscum contagiosum lesions are presumably common in IRIS but underreported. We point out this case for its striking clinical picture and well-documented relation to immunoreconstitution to draw attention to this IRIS manifestation.
The introduction and generalized use of highly active antiretroviral therapy (HAART) in HIV-infected patients has led to a substantial change in the spectrum of cutaneous disorders observed in these patients. There has been a decrease in most of the opportunistic infections and neoplasms previously very common in immunodepressed HIV patients, such as oral candidiasis, opportunistic fungi and mycobacteria, Kaposi's Sarcoma and Lymphoma . On the other hand, new entities have emerged as the Immune Reconstitution Inflammatory Syndrome (IRIS).
This syndrome affects patients during the initial phase of immunological reconstitution triggered by HAART in which CD4 lymphocyte counts rise and viral load decreases. This immunologic boost may lead to inflammatory manifestations mainly associated with preexisting infections, whether they have been previously diagnosed and treated or unrecognized. There is a paradoxical clinical deterioration after the introduction of HAART despite improvement of infection surrogate markers.
Immune reconstitution syndrome has first been reported as an immune recovery vitritis after initiation of HAART in patients with previous CMV retinitis . Since then, many other infectious agents have been reported in association with IRIS including M. avium complex (MAC), Mycobacterium tuberculosis, Criptococus spp., and Pneumocystis jirovecci . Other noninfectious diseases have also been reported in association with IRIS namely sarcoidosis and other granulomatous diseases.
In January 2004 a 65-year-old male patient presented with several papules of mollusca contagiosa (MC) in the genital area. He refused, at that time, any blood test evaluation. The patient was treated by two cryotherapy sessions after which he did not return to scheduled appointments.
In December 2004 he was admitted to the infectious diseases department of our hospital with a Mycobacterium tuberculosis milliary Infection and started on antibacillary therapy. He tested positive for HIV1 infection. The CD4 cell count was 51 cells/mm3.
In January 2005, he was readmitted to the infectious disease department; he was agitated, disoriented, had a slurred speech and ataxic walk. A lumbar puncture was not performed because a hypodense lesion with some mass effect was identified in the head CT scan; serum cryptococcal antigen was negative. Further evaluation revealed cerebral toxoplasmosis. He received appropriate therapy and was simultaneously started on HAART with lamivudine, zidovudine and nevirapine. The CD4 cell count had decreased to 34 cells/mm3 and the viral load was 53385 copies/ml (bDNA). At that time, he had no cutaneous lesions.
In April 2005 he returned to our dermatology department complaining of multiple cutaneous lesions that had suddenly appeared 2 weeks before (2 months after starting HAART). We then observed countless exuberant papules representing mollusca contagiosa on the neck (Fig. 1), right eyelid (Fig. 2), nose, pubic area, penis and scrotum (Fig. 3).
He was otherwise in general good condition and was being successfully treated for the two previous opportunistic infections. Surrogate infection markers had improved with a CD4 cell count rise to 188 cells/mm3 and decrease in the viral load to 78 copies/ml. Cryotherapy with liquid nitrogen was performed in only a few of the larger lesions (Fig. 4).
The patient returned for several followup evaluation appointments and in July 2005, a significant improvement was documented (Fig. 5); most of the lesions had spontaneously healed and there were only minor residual ones. Infection markers had further improved with a CD4 cell count of 225 cells/mm3 and a suppressed viral load (<50 copies/ml).
Immune reconstitution inflammatory syndrome mainly affects patients with low CD4 cell counts at the time of HAART introduction, most often <50 cells/ mm3  and that experience significant increases in CD4 cell count and marked reductions in HIV RNA levels .
Immune reconstitution inflammatory syndrome occurs as the immune system regains both microbe-specific activity and shifts towards an increasing inflammatory state following HAART. Thus antiretroviral treatment leads to an early rise in CD4-T memory cells (CD45+), followed 4-6 weeks later by the increase of naïve CD4-T cells (CD45RA+, CD62L+), with evidence of a better immunological response to microbial agents. Also, antiretroviral treatment shifts the balance between Th1 and Th2 responses, leading to increase of potent pro-inflammatory cytokines (IL2, IFN-γ) .
The interval between the start of HAART and the beginning of IRIS is highly variable, from 1 week to more than a year, but in the majority of cases it occurs during the first 2 months of HAART . Other risk factors associated with IRIS include male gender, shorter interval of time between starting treatment for an opportunistic infection and starting HAART, and antiretroviral drug naïvety at the time of diagnosis of underlying opportunistic infection .
Most of IRIS cases are self limited and require only symptomatic treatment, although in severe cases anti-inflammatory drugs or corticosteroids may be used. Only the cases in which IRIS causes serious damage, such as neurological disease or liver failure, should temporary interruption of HAART be considered .
Several skin manifestations have been reported in association with IRIS including herpes zoster and herpes simplex Infections, MAC infection, Hansen disease, Kaposi's sarcoma, Reiter's syndrome, sarcoidosis [3, 7], foreign body granulomas, acne vulgaris, and dishydrosis.
Molluscum contageosum lesions are very common in HIV patients . There are, in fact, reports of resolution of previously recalcitrant MC lesions after the beginning of HAART [8, 9]. In association with IRIS, however, cases of MC have not been reported often. MC has mostly been reported in case series  and also as an additional clinical finding in a patient reported with a granulomatous response to tribal medicine . We feel that MC associated with IRIS are probably very common, but underreported.
It is also important to mention that the differential diagnosis in an HIV patient presenting with waxy umbilicated papules with molluscoid appearance includes other entities besides molluscum contagiosum, the most important being disseminated cryptococcosis and dimorphic fungal infections such as histoplamosis, coccidiodomycosis and Penicilium marneffei infection . Disseminated cryptococcosis was considered unlikely in our patient as serum cryptococcal antigen was negative 3 months prior to the reappearance of cutaneous lesions. The other differentials were considered to be highly unlikely on the basis of epidemiological evidence as they are exceedingly rare in Portugal. Histoplasmosis is found mainly in southeastern-central US and Africa and coccidioidomycosis in southwestern US, Central and South America. P. marneffei is endemic to Southeast Asia .
In conclusion, our patient presented with a remarkable exuberant clinical picture and a very clear time relation between the appearance of cutaneous lesions and immunological reconstitution. Another important aspect to point out is that, in spite of the countless cutaneous lesions, there was spontaneous healing after the initial phase of immunological reconstitution, as is the usual result of most IRIS manifestations.
Being aware of cutaneous manifestations of IRIS is a new challenge that presents to dermatologists, particularly those that care for HIV patients; the recognition of IRIS should lead to appropriate diagnosis and avoid unnecessary interventions.
References1. Chen T, Cockerel C. Cutaneous manifestations of HIV infection and HIV-related disorders. In Bolognia J, Jorizzo J, Rapinni R, editors. Dermatology, Mosby 2003, p.1199-1215
2. Karavellas M, Lowder C, Macdonald C, Avila C, Freeman W. Immune recovery vitritis with inactive cytomegalovirus retinitis: a new syndrome. Arch Opthalmol 1998, 116(2):169-75
3. Hirsch H, Kaufmann G, Sendi P, Battegay M: Immune reconstitution in HIV-infected patients. Clin Infect Dis 2004; 38: 1159-66
4. Shelburne S, Visnergwala F, Darcourt J, Graviss E, Giordano T, White Jrº A, Hamill R: Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS 2005; 19: 399-406
5. Shelburne III S, Hamill R. The Immune Reconstitution Inflammatory Syndrome. AIDS Rev 2003; 5: 67-69
6. Goebel F: Immune reconstitution inflammatory syndrome (IRIS) - Another new disease entity following treatment initiation of HIV infection. Infection 2005; 33:43-45
7. French MA, Lenzo N, John M, Mallal S, McKinnon E, James I, Price P et al. Immune restoration disease after treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy. HIV Medicine 2000, 1: 107-115
8. Schulz D, Sarra G, Koerner U, Garweg J. Evolution of HIV 1-related conjunctival molluscum contagiosum under HAART: report of a bilaterally manifesting case and literature review. Graefes Arch Clin Exp Ophthalmol 2004; 242 (11): 951-5
9. Calista D, Boschini A, Landi G: Resolution of disseminated molluscum contagiosum with Highly Active Anti-retroviral therapy (HAART) in patients with AIDS. Eur J Dermatol 1999; 9 (3):211-3
10. Farrant P, Higgins E: A granulomatous response to tribal medicine as a feature of the immune reconstitution syndrome. Clin Exp Dermatol 2004; 29: 366-8
11. Chen T, Cockerell C: Cutaneous manifestations of HIV Infection and HIV-related Disorders. In Bolognia J, Jorizzo JL, Rapini RP (eds), Dermatology, Mosby 2003, pp 1199-1215
12. Sobera J, Elweski B: Fungal Diseases. In Bolognia J, Jorizzo JL, Rapini RP (eds), Dermatology, Mosby 2003, pp 1171-1198
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