This study used the clinical features of measles based on CDC criteria (1983) as the inclusion criteria, which consisted of fever, maculopapular rash, and any symptom between cough, coryza, or conjunctivitis . In areas with a high incidence of measles, the use of clinical criteria has a high diagnostic value, which is later confirmed by the positive anti-measles Ig M. These clinical criteria, however, have the opposite effect in areas with low incidence of measles. In this regards, the confirmation of IgM anti-measles using serology test is required [12, 38]. The validity of the clinical criteria is perfect when applied to measles eradication programs in areas with high measles incidence [12, 39] The WHO recommends the application of this clinical criteria (CDC 1983) to serve as the clinical presentation of measles in the measles eradication programme [13, 38, 39]. Several extradermatologic manifestations can also be found in measles cases. Most of such clinical findings regarding measles characterize the disease more cogently than others .
Because the signs and symptoms of measles are non-specific and patients with fevers and rashes can try to access any level of medical services, the relevant cases are easily missed [11, 13, 14, 30, 35, 41, 42]. Moreover, several patients showed some less typical features. As identification is always critical, including public health intervention , .the differential diagnosis of measles based on the erythematous rashes are many, including infectious diseases like rubella, parvovirus, Group A Streptococcus, adenovirus, non polio enterovirus, erythema infectiosum, infectious mononucleosis, and human herpes virus [5, 11, 14, 42]. Each disease has its own clinical manifestation since its early phase. Thus, it is important to obtain complete information about the history of a disease to make the correct diagnosis [9, 14, 16, 30, 42]. The normal pigmentation of a measles patient’s skin can also be used to predict the hyperpigmentation process. However, this hyperpigmentation feature may not always be seen in Caucasian people [16, 17].
Infectious diseases with hyperpigmentation are rare. Among six “old” diseases with classic exanthems, the first (measles) and second (scarlet fever) diseases can cause hyperpigmentation, but not the third (rubella), fifth (erythema infectiosum), and sixth (exanthema subitum) diseases. The fourth disease – referred to as Staphylococcal Scalded Skin Syndrome – can cause hyperpigmentation, but it involves a very different clinical manifestation compared to measles. Most of the literature regarding post inflammatory hyperpigmentation involves both infectious and non-infectious conditions. The non-infectious diseases are predominant, whereas the infectious diseases are limited [11, 14]. In the literature, postinflammatory hyperpigmentation are mostly caused by any form of inflammation, including infections and allergy-related developments. Skin insults can also result in inflammation and postinflammatory hyperpigmentation [17, 44,45,46]. The non-infectious causes of hyperpigmentation include drug associated reactions. Some drugs could be involved here, including the antiretro viral drug, interferon alfa, non steroidal anti inflammatory drugs, anti hypertensive, antimalarial drugs, and antibiotics [47,48,49,50]. .Some forms of postinflammatory hyperpigmentation are more obvious in people with darker skin colors . Hyperpigmented rashes in measles may follow the same pathway but the data required to determine the same trend is very limited.
In individual setting, the early phase of measles will not show hyperpigmentation, and so this clinical appearance has low value for early diagnoses. However, in an outbreak setting or elimination program, the identification of several early cases is important for the existing community’s benefit. Identifying measles can be possible in some early patients instead of steering the focus towards only one child. Any misclassification of measles case could potentially have considerable impacts, because the patient becomes a source of infection. In an outbreak setting, identification in the initial phases and subsequent prevention of the spreading of the disease is very important. In our setting, even in the outbreak situation, the IgM examination was mostly not available. Clinical manifestations give out important information. The identification of measles in low-prevalence area is more difficult because of the limitation of health workers’ clinical experiences and because many diseases show similar signs and symptoms [12, 13, 39].
The anti-measles Ig M in the appropriate clinical situation ensures the laboratory confirmation of measles [4, 5, 9, 13, 16, 41]. Immunity to measles might not be absolute but depend on the level of preexisting antibodies. The intensity of exposure is also an important factor here . For some clinicians, the distinct morphological features and the distribution of the erythematous rashes, along with a particular cluster of systemic appearances, may give the necessary clues. Careful physical diagnosis entails a complete examination of the rashes and the features of systemic involvement . Hyperpigmentation adds significant value with respect to the identification of measles [4, 5, 11].
In this study, all the patients underwent blood tests 3 days after the onset of the symptoms, and their maculopapular rashes became hyperpigmented and desquamated along the course of their illness. Seventy-five (or 91.5%) out of eighty-two subjects showed positive results with respect to anti-measles IgM. This result corresponds with some previous studies that found 70% positivity of IgM anti-measles when it was performed 3 days after the onset of rashes. The WHO states that 30% of all cases of measles showed negative anti-measles Ig M when the blood tests were performed on the third day since the first symptoms had appeared [38, 52] This result emerged because the anti-measles Ig M has not yet been established at that time. Ig M antibody coincided with the appearance of rashes on the skin of a measles patient. If the blood tests were performed on the third day after the onset of rashes, the Ig M would have been positive in 70% of the cases. Further, when the samples were taken on the seventh day of illness, all cases showed positive anti-measles IgM  The sensitivity of anti-measles Ig M can be as high as almost 100% when conducted at least 3 days after the onset of rashes [52, 53]. In developed countries where measles cases have nearly disappeared, the positive predictive value of IgM serology decreases as more false positives are obtained. False positive results can occur because of non specific reactions, the interference of rheumatoid factor, or other infections such as parvovirus B19, Human Herpes Virus (HHV) 6, or rubella . .On the other hand, in low-incidence countries, the NPV would be higher . Anti-measles virus IgM would persist till at least 4 weeks after the rash . In older vaccinated children, measles cases can be associated with the weaning of antibodies. This possibility is quite high especially if children only receive measles vaccination once in their lives. For such children, the dynamics of IgM and IgG should be considered and other diagnostic tests might also be needed [52, 54].
Many participants in this study had nutritional problems. Malnourishment caused immune system disturbances. Indeed, measles infection leads to more problems, both in the nutritional and the immunity aspects. Subjects with measles infections tend to have lower body weights than average children [11, 55]. The measles rashes in malnourished children tend to result in greater confluence and progresses to become dark red in color. Desquamation is marked and occurs in a large scale .
This study also showed the difference between younger (less than 1 year old) and older children. A study in Hong Kong by Chan et al. showed a similar comparison in the period between 1999 to 2008. They found that the younger children had modified clinical appearances. This group had shorter duration of fever, earlier appearances of rashes, and fewer incidences of conjunctivitis and hyperpigmentation. There were no differences regarding cough, coryza, Koplik’s spot, and other related compications . Their results are different from ours. Our younger children had more coryza, Koplik’s spot, and other complications, albeit fewer instances of cough, conjunctivitis, and hyperpigmentation, as showed in the Table 3.
A study by Ciccone et al. with 463 participants found the clinical features of measles patients as follows: fever (85%), rash (97%), cough (46%), coryza (48%), and conjunctivitis (17%) . In the study by Chan et al. 165 subjects were recruited, with the following proportions of clinical features: fever (100%), rash (100%), cough (96.4%), coryza (98.25%), conjunctivitis (58.2%), and Koplik’s spot (75.2%) . In our study, all the patients had fever, rash, and at least one of cough, coryza, or conjunctivitis, signs and symptoms which were part of the inclusion criteria.
Although the pathogenesis is not well-known, skin manifestation can be the result of the dissemination of infectious agents from distant sites or via direct inoculation to the cutaneous surface. It also may result from immune or cell mediated responses in the skin . The erythematous rashes in measles patients can be potentially explained by the infection of the dermal endothelial cells and keratinocytes, which are later cleared by the host cells’ immune response [58, 59]. Rashes are manifestations of the measles virus-specific type 1 CD4 and the CD8 T-cell adaptive immune response, along with lymphocyte infiltration into the tissue sites of virus replication, and they coincide with the clearance of the infectious measles virus . The immunocompromised patients often do not develop skin rashes following measles infection  Clearance of the virus and the resolution of the rashes are both associated with recovery in almost all children. However, some viral ribonucleic acid (RNAs), like those found in a study in Zambia, persist in multiple locations long after the measles virus is no longer detected [54, 60].
These hyperpigmented rashes is presumably caused by delayed hypersensitivity response against virus antigen . The study by Chan et al. found that hyperpigmented rashes were found in 83% of all the participants . In this study, nine children did not show hyperpigmented rash. This was maybe related with the antibodies received from mothers or vaccinations .
Koplik’s spot was considered as a pathognomonic sign of measles virus infection [35, 62, 63]. In this study, the specificity and positive predictive value of Koplik’s spot were both 100%. All patients with Koplik’s spot had positive anti-measles Ig M. This spot was not sensitive because many participants in our study came while rashes had already spread all over their bodies. The Koplik’s spots are usually seen since 1–2 days before until 1–2 days after the onset of the first rash [11, 15, 35, 50]. Other researches found that only 47.4% of the total participants had Koplik’s spots, with a specificity of 86.1% . A review by Perry and Halsey mentioned that Koplik’s spot would only be noticed among 60–70% of measles patients . A study by Zenner et al. in London revealed that the PPV of clinically suspecting measles was 50%, but with Koplik’s spot this PPV would improve to 80%. The sensitivity and specificity in the above study were 62.5 and 86.1%, respectively . In Japan, Kimura et al. showed that the sensitivity and specificity of Koplik’s spots as the diagnostic marker for measles were 48 and 80%, respectively. Out of the 3023 participants in this study,only 717 had Koplik’s spots. The positive rate of these spots in patients with other viruses detected were approximately 20–30%. In conclusion, the Koplik’s spots did not indicate a specific manifestation of measles, although the concomitant specificity related to measles was quite high .
In our study, the combination of fever, maculopapular rash, and the hyperpigmented rash had 90.7% sensitivity, 28.6% specificity, 93.2% positive predictive value and 22% negative predictive value. Mc Nemar and Kappa test results for hyperpigmented rashes showed p values of 0.774, and 0.119, respectively. The percentages of the clinical features of fever, maculopapular rashes, and hyperpigmented rashes in our study were similar to those found by Chan, especially in subjects under 1 years old. In this study, hyperpigmented rashes occurred in 137 (83%) of all the participants. Conjunctivitis and hyperpigmented rash were deemed as two significant clinical symptoms of measles viral infection . Another study in the United Kingdom by Ramsay et al. found that the combination of fever, cough, coryza, and conjunctivitis were non-discriminatory and were broadly similar for many groups with confirmed infections . On the other hand, no specific clinical features were consistently associated with Group A Streptococcus (GAS), parvovirus B19, or even HHV 6 infections . Most scientific articles related to hyperpigmentation described the postinflammatory hyperpigmentation, albeit within a very limited portion of infectious diseases . In non-infectious diseases, hyperpigmentation could be found in relation to many conditions such as acne, atopic dermatitis, psoriasis, impetigo, lichen planus, pytiriasis rosea, allergic and photo-contact, drug reactrion, effect of laser therapy, and insect bites .
In their study, Hutchins et al. reported the sensitivities and specificities of four studies using the same clinical variables that were used in our research (fever, rashes, and at least one of cough, coryza, and conjunctivitis; serological confirmation by IgM or enzyme immunoassays (EIA)). In Florida, California, and New York in the 1980s (182 participants), the sensitivity, specificity, the PPV, and the NPV of the clinical case definition were 88, 48, 74, and 70%, respectively. In New York between 1994 and 1995 (99 participants, between 1 and 14 years old) and in Venezuela between 1993 and 1995 (379 participants, between 1 and 14 years old), the sensitivity, specificity, PPV, and NPV values were 50, 69, 4, and 98%, and 76, 51, 35, and 86%, respectively. The fourth study in Suriname (121 participants, 52% of who were < 5 years old, and 15% were 15 years old or older) showed the sensitivity, specificity, PPV, and NPV values of 100, 23, 1, and 100%, respectively. The sensitivity values of those studies was somewhat similar or lower than our results, while the specificity values were higher than ours. All four studies considered different incidences of measles. The low incidence of measles churned out low specificity and PPV values .
In our study, the inclusion criteria included fever which limits the possibility of non-infectious diseases, although several allergic and immunological diseases could also entail fever . The high sensitivity value (90.7%) for fever, maculopapular rashes, and hyperpigmented rashes in our study indicates that these parameters can be used for screening with respect to measles surveillance. However, a diagnostic tool is valid only for the Mc Nemar test with p ≥ 0.05 and for Kappa values with p < 0.05. Therefore the combination of fever, maculopapular rashes, and hyperpigmented rashes (combined with either cough, coryza, conjunctivitis, and Koplik’s spot) could not be used as a replacement of the anti-measles IgM value.
In practice, when we found suspicious cases of measles, and became surer about our diagnosis by evaluating the hyperpigmentation of our patients, we could follow the outbreak protocol in our community. Indeed, we do not have to wait for the IgM examination to be available. However, if it is available, we can confirm the clinical findings with the IgM examination itself and use it to prevent the further spread of the disease. Once again, the benefit of this hyperpigmentation is more at epidemiological level.
To our knowledge, the study of clinical manifestation focusing on hyperpigmentation in measles disease remain very limited in the existing literature [11, 16, 56, 66]. There may be variations in clinical appearances among patients in many countries. This study can provide be a base upon which the Ministry of Health in Indonesia can modify its diagnosis criteria by including hyperpigmentation, while the initial erythematous rash disappears, as one of the screening tools to diagnose measles within an outbreak setting. Lower predictive values emphasise the importance of the local contexts of the patients and the epidemiological variations, as described in other studes about Koplik’s spots .
This study was limited to a single-center. Most of our children were Javanese in ethnicity and had the skin type IV-V (Fitzpatrick skin types IV-V). Children with skin type VI can only found in the eastern part of Indonesia and not included in our study. Hyperpigmentation is rarer in Caucasian people. In general, people with darker skin tend to have more common hyperpigmentation [16, 17, 67]. The other limitation was related to the usage of PCR: we did not use PCR as the gold standard, since the WHO recommendations accept the anti-measles IgM as well. We also did not examine other causes of the disease (with maculopapular rashes) in this study. Some definitive laboratory examinations were not available in our country.
At the moment, measles is included in a short list of potentially eradicable disease [2, 13]. As the developing country with low coverage of vaccination and high incidence of measles, Indonesia is still likely witness more outbreaks in the future. The higher vaccination coverage is the key factor that can tackle this problem, as seen in many other countries [2, 13, 20,21,22, 31, 68]. The ability to diagnose based on clinical appearances in most of the measles cases is imperative. In addition, rapid and prompt feedback to public health officers is crucial for timely interventions [14, 22, 52]. The outbreak setting is certainly different from the individual patient approach within the clinical settings.