**8. Conclusions and prospects**

*Viruses and Viral Infections in Developing Countries*

In contrast with the classic measles infection, the atypical measles syndrome occurs in older patients, often presenting with a heterogeneous rash, pulmonary infiltrates, hepatic dysfunction, and eosinophilia. The formation of immune

complexes has been proposed as responsible for the manifestations of the syndrome [58]. This self-limiting disease, may show, however, long lasting, asymptomatic pulmonary nodules. An immune waning is suspected to occur in this disorder, though such an event has been refuted with measles virus infection at large. Officially, patients with this syndrome have been reported as recently as 2015 [59].

The atypical measles syndrome (AMS) stands out when compared with classic

Clinically, the AMS does not resemble the classic MV disease and is usually mild. GPs have difficulties in making the diagnosis in real time. Anti-MV antibody titers are higher than 1:160, which is very unusual for classic measles. In AMS, Koplik spots are frequent and mostly will last 5–7 days, while they last rarely more than 2 days in the classic disease. Photophobia is rarely present in AMS. AMS is probably

While most cases of AMS in the 1960s were associated with FIMV, the more recent occurrences have been associated with the live attenuated measles vaccine (LAV). Vaccination with FIMV had offered protection for a few months, after which the titers dropped suddenly [61]. We have suggested that this drop of antibody titers is most consistent with a humoral immunity waning. Cases of AMS with prior LAV vaccine have been reported, which are consistent with secondary vaccine failure. Such cases have been suggested to follow a prolonged exposure to an acute

To confirm the ease by which the diagnosis of AMS is missed, 291 recruits were diagnosed with measles in 1987. They were young adults, with abdominal pain, diarrhea, and vomiting (33%); Koplik spots lasting a mean 7 days; and abnormal liver function tests (86%). The diagnosis of AMS was missed. Retrospectively, this was most certainly the diagnosis, although no anti-MV titers have been

In 2015, Levine et al. reported on the status of the measles immunity, 20 years after the two-dose MMR vaccine was introduced. Of the cohort of recruits in 1996, 95.6% had shown positive anti-MV antibodies. In 2007, this positive data had dropped to 85%. Although the authors did not dare to make the statement, this

To summarize this issue, we have showed that the AMS differs from typical measles by various features. This is probably a disorder of immunologic nature, involving immune complexes. The AMS is presently rare, but to our opinion, this may be due to a notable under-diagnosis. The association between the AMS pathogenesis and immune waning should be confirmed. It is not excluded that this disorder be related with carcinogenesis as well [65, 66], as it has been proposed that a persistent viral infection is required for virus-associated carcinogenesis [67] and

reflected a state of waning immunity, to our opinion [64].

that a waning immunity might lead to a persistent MV infection.

AMS presents at an older age, often with a high and prolonged fever. A polymorphic rash starts in the hands and feet. In the lungs, this disorder shows nodular infiltrates together with swollen hilar lymph nodes. These changes may regress suddenly. Liver function tests are often abnormal in AMS. Eosinophilia is frequent. This disease entity was first described in 1963, following the vaccination with the formalin inactivated measles virus (FIMV) vaccine. A subsequent exposure to the wild type MV has often been identified. The FIMV vaccine is said to have been withdrawn in 1967, but new cases of AMS were still reported in 2015 [59].

**7. The atypical measles syndrome**

measles for the following reasons.

not contagious [60].

measles patient [62].

reported [63].

**152**

A relationship between MV expression and CHL was provisionally established on IHC [positive with two antigens or more in 82 of 154 CHL patients]; on RT-PCR [positive in 4 of 15 cases for HA-MV RNA; for 2 of 16 NP-MV RNA], and on *in situ* hybridization [for 2 of 7 CHL with HA-MV RNA; in 8 of 21 for NP-MV RNA], as well as with several other malignancies. When focusing on CHL, this association may even be causally linked: apoptosis regulation by the MV may be one of the supportive mechanisms. Our findings are probably sustained by an increasing CHL morbidity related with a progressing occurrence of measles in young adults, in Israel [68], in Quebec [69], and in Connecticut [70], in which frequent outbursts of measles are described.

A clinicopathological correlation, based on the IHC results, was chosen, mainly due to the frequent results as compared with RT-PCR and *in situ* hybridization. In this part of our study, we confirmed an association between CHL and the MV. More females, NS-CHL cases, and more patients in the early stages of their disease were linked to the expression of MV in their tissues. In spite of these variables being, as a rule, correlated with a better prognosis, when they are associated with a positive measles expression, the net effect is a poor prognosis [3].

Regarding the refutation of our findings and conclusions by the German group, this might have been an occasion for further learning. However, the repercussions thereof, on our thesis and our findings, were such that no future was available for us in this domain. As a colleague described it, our position and our theory had been buried. Moreover, I never understood why it was done in that most unpleasant way.

A chapter on the atypical measles syndrome was introduced at the end of the study. This disorder is related with measles and with the MV, but the link has not been clarified completely. Most of the AMS features, clinical, radiological, and biological, differ completely from those of measles. While measles is predominantly an infectious disease, and is highly contagious, AMS is probably not contagious, with its pathogenesis probably based on the formation of immune complexes. One of the highlights of the AMS is an anti-measles antibody titer of 1:160 or higher, much beyond that found in measles. Our interest, at this point, laid in evidence pointing toward immunity waning, as an essential component of AMS. Moreover, in the presence of a sharp drop in the titer, following mainly the FIMV vaccination, as well as occasionally that of the LAV vaccine, the subject might be submitted to the protracted exposition to an acute measles patient. So far, we are not aware of cancer developing in the context of AMS cases, but, since this disorder is often missed, it might be worthwhile looking for cases of cancer within such a context [60].

The prospects and suggestions for proceeding with our research include an epidemiologic study as well as the duplication of our basic investigation, but this once by scientists of good faith. The epidemiologic investigation should have 3 components: the first two, based on our CHL cohort, about half of which show IHC evidence of the MV. Of this population, we will attempt to identify, via the Israeli Ministry of Health Registry, patients who had contracted measles as well as those who had been vaccinated for MV, including vaccination details. The third will deal with AMS, based on the cohorts highlighted by Giladi M et al. [63], and Levine H et al. [64]. Confirmation in the first of the diagnosis of AMS, and research of patients with possibly MV-related tumors and in the second, confirmation of the relevance to immune waning.
