First Reported Case of Puerperal Immune Reconstitution Inflammatory Syndrome With Multiple Systemic Manifestations in an HIV-Positive Woman: A Case Report and Structured Literature Review

Abstract

Introduction

Immune reconstitution inflammatory syndrome (IRIS) is a recognized complication of antiretroviral therapy (ART) in people living with HIV, typically presenting as a single opportunistic infection. Concurrent multisystem IRIS, particularly during the puerperium, is extremely rare.

Case Presentation

We report a 27-year-old woman newly diagnosed with HIV during the third trimester of pregnancy who initiated dolutegravir-based ART at 35 weeks’ gestation. Three months postpartum, she developed multiple concurrent IRIS manifestations, including oral candidiasis, Kaposi’s sarcoma, severe thrombocytopenia, severe anemia, pulmonary embolism, viral pneumonitis, cholangitis, and peripartum cardiomyopathy. Published literature identified very few cases of three or more simultaneous IRIS events after ART initiation, with no previous reports describing such extensive multisystem involvement in the puerperium.

Conclusion

This appears to be the first reported puerperal case of extensive multisystem IRIS. We propose the term “IRIS multiplex” to describe patients presenting with five or more concurrent IRIS manifestations, as a hypothesis-generating concept for future research.

Introduction

IRIS is a paradoxical inflammatory response from rapid increase in CD4+ and CD8 T+ cells, dysregulation of innate immune activation, macrophage activation and excessive cytokine production that occurs predominantly during the first six months of ART initiation, re-initiation, or optimization in about 10%-20% of HIV-positive patients.^1,2 Because IRIS can take on a broad spectrum of clinical manifestations from mild to life-threatening disease conditions, they often involve infectious, autoimmune, endocrine, neoplastic, dermatologic, pulmonary, hematologic, pulmonary, gastrointestinal and neurologic syndromes. These syndromes generally pose therapeutic and diagnostic challenges presenting either as paradoxical IRIS or unmasking IRIS.

IRIS remains a critical contributing factor to early morbidity and mortality among patients initiating ART with advanced HIV disease. Current evidence suggests that rapid restoration of adaptive immunity following ART is accompanied by dysregulated innate immune activation, excessive cytokine production, macrophage activation, and expansion of pathogen-specific CD4+ and CD8+ T lymphocytes. After childbirth, rapid reversal toward a pro-inflammatory Th1-dominant immune response occurs as maternal immune homeostasis is restored.

In pregnant women living with HIV who initiate ART late, puerperal immune rebound may accentute immune restoration and increase susceptibility to IRIS. Notwithstanding, several IRIS conditions with multiple systemic involvement presenting in a single HIV positive patient are extremely rare or otherwise unreported.

Herein, we describe a postpartum woman with advanced HIV disease who developed multiple IRIS manifestations highlighting multiple systemic involvement following ART initiation during late pregnancy. Based on this unique presentation and review of the literature in this regard, we hereby advocate the use of the new nomenclature “IRIS multiplex” for patients who develop five or more IRIS manifestations.

Case Presentation

A 27-year-old newly diagnosed HIV-positive woman was diagnosed during a routine antenatal visit at 35 weeks of gestation in June 2024. She had no previous history of chronic medical illness, and was immediately commenced on tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD), the nationally recommended first-line ART regimen in accordance with the current 2022 consolidated guidelines for the prevention and treatment of HIV and AIDS in Uganda. At the time of ART commencement, she was generally in good health; and baseline CD4 counts were 196cells/µL(6.69%). Unfortunately, the baseline HIV viral load could not be done because of financial limitations. In spite of this, she reported 100% adherence throughout the duration of treatment. Approximately four weeks following ART initiation, her pregnancy was terminated by an emergency cesarean section due to fetal distress in July 2024, at 39 weeks of gestation.

In September 2024, she presented with an eight-week history of dry cough, unintentional weight loss of>10% of body weight, low-grade fevers, loss of appetite, drenching night sweats, orthopnea, easy fatigability, hyper-pigmented skin lesions on both feet, palpitations, bilateral lower limb edema, and nodular swellings in the neck and axillary regions, which prompted admission. There was no associated history of difficulty in breathing, nasal discharge, nausea, vomiting, excessive salivation, body weakness, dizziness, heartburn, diarrhea, headache, loss of balance, convulsions, mental status change, neck stiffness, or visual blurring. Additionally, there was no history of smoking, alcohol consumption, illicit drug use, or suggestive of chronic ailments - diabetes mellitus or hypertension. The patient's medical, surgical, and occupational history was unremarkable. She, however, reported 100% adherence to HAART.

Physical examination revealed a fully conscious, sick-looking patient with mild pallor, afebrile, who had a purplish lesion in the tonsillar area, mild oral thrush, significant cervical and axillary lymphadenopathy, and non-tender, bilateral pitting edema of the lower limbs. Cardiac examination revealed a sinus tachycardia of 118 beats/min, blood pressure = 92/50 mmHg, and heart sounds 1 and 2 were heard and normal. Respiratory examination revealed a tachypnea of 32 breaths/min, flaring of the alae nasae with fine basal crepitations, and oxygen saturation of 88% on room air. Abdominal examination revealed a distended abdomen, non-tender, with no palpable organomegaly. There were no significant findings in the central nervous, ophthalmic, urogenital, and musculoskeletal systems.

CD4 counts were 196cells/µl (6.69%), prompting investigations for advanced HIV disease - a urine Alere lipoarabinomannan (LAM) (Alere, Waltham, Massachusetts), serum CRAG, and toxoplasmosis titers, all of which were negative. Chest x-ray demonstrated bilateral opacities, loss of costophrenic angles, Kerley B lines, a silhouette sign, and cephalization, consistent with heart failure (Figure 1). A cardiac echocardiogram showed features of viral pneumonitis, peripartum cardiomyopathy, and a mild pericardial effusion in early tamponade. An abdominal/pelvic ultrasound scan showed bilateral gross pleural effusion, mild ascites, mild hepatomegaly, and multiple enlarged abdominal lymph nodes around the porta hepatis, along the abdominal aorta, and left inguinal region.

Figure 1.

CXR showing bilateral opacities, loss of costophrenic angles, Kerley B lines, a silhouette sign, and cephalization

An emergency chest CT angiography scan revealed features of bilateral and extensive pulmonary embolisms involving the lobar, segmental, and sub-segmental branches, as well as massive bilateral pleural effusions (right greater than left) with associated postero-basal comprehensive partial lung atelectasis (Figure 2). Renal and liver function tests were essentially normal. Right-sided pleuralcentesis was done, drawing approximately 2L of straw-colored fluid, and the gene expert was negative.

Figure 2.

CT scan showing bilateral and extensive pulmonary embolisms involving the lobar, segmental, and sub-segmental branches, as well as massive bilateral pleural effusions (right greater than left) with associated postero-basal comprehensive partial lung atelectasis

In addition to continuing ART, a cervical lymph node biopsy was conducted, and she was initially started on furosemide, carvedilol, spironolactone, enalapril, and oxygen therapy. However, two weeks following admission, clinical assessment showed severe oral-esophageal candidiasis and severe pallor of the mucous membranes with the complete blood count showing a hemoglobin level of 5.0g/dl (11.0–13.0), HCT = 24.9% (45-52), MCV = 79.6fL (84-96); PLT = 20x10³/uL (50-400x10³/uL), which warranted blood transfusion with whole blood and packed red blood cells. In addition to blood transfusion and the previous treatment, dapzin, metolazone, isosorbide mononitrate, fluconazole, oraxin, fastum gel, colchicine, bromocriptine, and anticoagulant therapy were added.

Because of the spectrum of illnesses that she had been diagnosed with, bi-weekly psychotherapy sessions were arranged in addition to direct observed treatment strategy (DOTS) to ensure adherence to the treatments.

The liver function tests revealed elevated transaminases: AST 122 U/L (0-40), ALT 57 U/L (5.3 – 40), and GGT 85U/L (8-41). The serum cryptococcal antigen and rapid COVID-19/influenza nasopharyngeal PCR tests were negative. Unfortunately EBV, CMV, and HSV PCR assays could not be done because of financial constraints.

Eight weeks into her admission, clinicians observed hyper-pigmented skin lesions on the feet had increased in number, size, and had spread to occupy the lower half of the lower limbs. On examination, the patient had violaceous papules, and plaques which were biopsied and confirmed as Kaposi’s sarcoma.

A comprehensive list of diagnoses was made to guide clinical management at that point: i) Oral candidiasis IRIS, ii) Peripartum cardiomyopathy IRIS, iii) severe anemia IRIS, iv) Severe thrombocytopenia IRIS, v) bilateral and extensive pulmonary embolisms IRIS, vi) HIV-associated cholangitis IRIS, vii) viral pneumonitis IRIS, and viii) Kaposi’s sarcoma IRIS.

After about eight weeks of ensuring the resolution of the multiple immune reconstitution inflammatory disease conditions, in addition to emphasizing adherence to HAART. At the point of diagnosis with Kaposi’s sarcoma IRIS, before referral to the National Cancer Institute for additional oncological management, a repeat CD4 count was 254cells/ul, demonstrating an increase in CD4 counts, and her viral load was found to be undetectable.

The patient was referred to the National Cancer Institute, where chemotherapy and radiotherapy were provided. Follow-up of the patient nine months later showed complete regression of Kaposi’s sarcoma skin lesions, sustained viral suppression and excellent ART adherence. A summary of the chronological timeline of clinical events is shown in Table 1.

Table 1.

Chronological Timeline of Clinical Events

Time	Clinical event
35 weeks’ gestation (June 2024)	Newly diagnosed HIV infection during routine antenatal screening
Same day	Initiation of TLD (Tenofovir/Lamivudine/Dolutegravir)
Baseline	CD4 = 196 cells/μL (6.69%); baseline viral load unavailable
39 weeks’ gestation (July 2024)	Emergency Caesarean section for fetal distress
4–8 weeks postpartum	Progressive cough, weight loss, night sweats, dyspnoea, orthopnoea, oedema, lymphadenopathy and skin lesions
September 2024	Hospital admission
Admission	Advanced HIV investigations negative (urine LAM, serum cryptococcal antigen, toxoplasmosis serology)
Week 1	Chest radiograph, echocardiography, abdominal ultrasound, CT pulmonary angiography, thoracentesis
Week 2	Severe oral/oesophageal candidiasis, severe anaemia, thrombocytopenia requiring transfusion
Weeks 3–7	Multidisciplinary management, anticoagulation, heart failure therapy, antifungal treatment, psychological support
Week 8	Progressive violaceous skin lesions biopsied and confirmed as Kaposi sarcoma
Week 8	Repeat CD4 = 254 cells/μL; HIV viral load undetectable
Discharge	Referred for oncology management while continuing ART
Nine months	Complete regression of Kaposi sarcoma lesions and sustained virological suppression

Methods

Study Design

This study comprises a detailed case report of an HIV-positive postpartum woman who developed multiple inflammatory conditions following ART initiation and a structured literature review of previously published case reports and case series describing multiple IRIS presentations in HIV-positive persons following ART initiation.

Search Strategy

Our search was conducted from November 11^th, 2025, to December 31^st, 2025. We considered papers that reported concomitant HIV infection and many immune reconstitution inflammatory syndromes/multiple reconstitution inflammatory syndromes with sufficient detail from 1988 to the end of December 2025. The search strategy combined Medical Subject Headings and free-text terms using Boolean operators “multiple immune reconstitution inflammatory syndromes after antiretroviral therapy”, “many immune reconstitution inflammatory syndromes after antiretroviral therapy” AND “AIDS” or “HIV positive” limiting the search to humans via Scopus, Google Scholar, Science Direct, Hinari, Scielo, ProQuest, Semantic Scholar, ResearchGate and Medline database from the PubMed website. Searches were limited to: English language publications and publications available up to 31^st December 2025.

Article Selection

Articles were selected if all of the following categories were considered positive HIV serology, an increase in the CD4 count after HAART initiation, multiple IRIS diagnoses, OR many IRIS diagnoses (three and above), treatment outcome, gender, and age.

Eligibility Criteria

Publications were eligible if they satisfied the following criteria: confirmed HIV infection, initiation of ART preceding clinical deterioration, at least three distinct IRIS manifestations, and publications (case reports, case series or brief clinical communications). Full-text papers were then assessed by the criteria outlined above, and additional papers were derived from a comprehensive analysis of the reference lists of retrieved articles.

Exclusion Criteria

Publications were excluded if they involved HIV-negative patients, represented review articles without original patient data, lacked sufficient clinical details, described only one IRIS manifestation, editorials, expert opinions and conference abstracts without adequate information.

Data Extraction

Using a standardized data collection form, variables that were extracted were: first author, publication year, country, patient age, sex, baseline CD4 count, baseline HIV viral load (were available), repeat viral load, type and number of IRIS manifestations, organ systems involved, time from ART initiation to IRIS, clinical management, and outcome. For this case, additional variables were extracted including: gestational age at ART initiation, timing of delivery, postpartum interval, evidence supporting immune recovery and alternative diagnoses considered.

Data Synthesis

Given the rarity of reported cases, quantitative meta-analysis was not feasible. A descriptive narrative synthesis was therefore performed. Continuous variables were summarized using medians and interquartile ranges, whereas categorical variables were presented as frequencies and percentages. IRIS manifestations were grouped according to systemic involvement to facilitate comparison across studies.

Literature Review

To date, our search strategy has identified nine publications (Figure 3) regarding HIV positive individuals who had developed three or more IRIS events following HAART initiation.^3-11

Figure 3.

Consolidated Standards of Reporting Trials (CONSORT) flow diagram of literature search. [MeSH = Medical Subject Headings]

Database search identified 54 titles or abstracts, of which 18 were excluded because they did not describe multiple/many immune reconstitution inflammatory syndromes after antiretroviral therapy (Figure 3). The remaining 36 articles underwent full-text review, and their references revealed four additional articles related to multiple immune reconstitution inflammatory syndromes after antiretroviral therapy, ‘IRIS’, AND ‘AIDS’ OR ‘HIV positive’.

Of these 40 articles, 31 articles were excluded because they involved non-HIV populations, lacked sufficient clinical detail, described only one IRIS event, or did not fulfill the predefined eligibility criteria outlined above. Five publications fulfilled the eligibility criteria from the database search and reference screening identified four additional eligible publications.

Consequently, nine publications were identified and included in the final review (Table 2); a third were females, while males predominated (67%). The median age of the patients was 38 years [(IQR: 25.5-48), (range: 1-55 years)]. Baseline CD4 counts were low across all studies (range: 2-47cells/µL), reflecting advanced HIV disease before ART initiation.

Table 2.

Clinical Characteristics of HIV Positive Patients Diagnosed With multiple IRIS Following initiation of ART Reported in the Literature

Author	Year	Age/Gender	Country of origin	Baseline HIV VL (copies/ml)	Baseline CD4 (cells/ul)	Repeat HIV VL (copies/ml)	Repeat CD4 (cells/ul)	IRIS diagnoses	Systems involved	Duration to IRIS diagnosis (days)	Outcome
Achappa B et al 3	2012	40/M	India	N/A	22	N/A	107	Cryptococcal meningitis, Toxoplasmosis, & CMV retinitis (3)	Central nervous and ophthalmic systems (2)	71	Improved
Asselman V et al 4	2007	38/M	South Africa	N/A	9	N/A	30	Tuberculosis, cryptococcosis & varicella zoster virus (3)	Pulmonary and dermatologic systems (2)	10	Improved
Laverde-Sudepe N, et al 5	2019	55/F	USA	N/A	4	undetectable	68	Disseminated histoplasmosis, cerebral toxoplasmosis, & oral candidiasis (3)	Pulmonary, gastrointestinal, and central nervous systems (3)	28	Improved
Mitroi-Maxim C, et al 6	2014	42/M	Romania	N/A	Low	N/A	N/A	Cryptococcus neoformans meningoencephalitis, TB meningoencephalitis, CMV encephalitis, severe bacterial infections, systemic candidiasis, HSV ulcerative stomatitis and esophagitis (6)	Central nervous, gastrointestinal, and hematologic systems (3)	N/A	Fatal
Yu L, et al 7	2025	54/M	China	N/A	7	<100	55; 247; 422	Primary immune thrombocytopenia, latent autoimmune DM, Hashimoto thyroiditis (3)	Hematologic and endocrine systems (2)	124	Improved
Riley S, et al 8	2024	26/M	USA	1,590,000	47	60	26	PJP, CMV, HHV-8, Cryptosporidium, EBV, HSV, Histoplasmosis (7)	Pulmonary, Gastrointestinal, hematologic, lymphatic (4)	21	Improved
Almeida-Silva F, et al 9	2016	33/M	Brazil	N/A	20	N/A	291	PJP, C. neoformans, disseminated histoplasmosis (3)	Pulmonary, musculoskeletal (2)	42	Improved
Thanh NT, et al 10	2016	25/F	Vietnam	N/A	2	N/A	96; 170	T. marneffi and methicillin-sensitive S. Aureus dermatitis and PTB (3)	Dermatologic and Pulmonary (2)	153	Improved
Potanski R, et al 11	2024	1yr 8/12mths/F	Argentina	1,000,000	456 (14%)	338	506(13%)	CMV, EBV, hemophagocytic lymphohistiocytosis (3)	Musculoskeletal, hematologic (2)	10	Improved
Present case	2025	27/F	Uganda	N/A	196	undetectable	254	Oral candidiasis, Peripartum cardiomyopathy, severe anemia, severe thrombocytopenia, bilateral and extensive pulmonary embolisms, HIV-associated cholangitis, viral pneumonitis, and Kaposi’s sarcoma (8)	Gastrointestinal, cardiovascular, hematologic, pulmonary, hepatobiliary, and dermatologic systems (6)	56	Improved

Across the nine publications, 34 IRIS manifestations were identified. Of the nine publications, only 2/9 (22%) described more than five IRIS manifestations,^6,8 while the rest exhibited three IRIS manifestations.^3-5,7,9-11 A fatality rate of 1/9 (11%) was observed in one of the patients who exhibited more than five IRIS events. ⁶ The most frequent conditions in patients exhibiting three or more IRIS events were cryptococcal disease (4/9, 44%)^,3,4,6,9 and cytomegalovirus disease (4/9, 44%).^3,6,8,11 The median time between ART initiation and the onset of IRIS events was 35 days [(IQR: 15.5-97.5), range: 10-153].

The highest number of cases was reported from the USA, including one of the two cases that exhibited more than five IRIS conditions.^5,8

Regarding systemic involvement, in the majority of patients (5/9, 56%)^,4,5,8-10 the pulmonary system was the most affected, followed by central nervous system, gastrointestinal tract, dermatologic system and hematologic system while the least affected systems were the lymphatic, ophthalmic, and endocrine systems (1/9, 11%).^3,7,8

Clinical outcomes were generally favorable following IRIS-specific therapy and ART continuation. Only one patient with extensive multisystemic IRIS died, illustrating the potential severity of overwhelming inflammatory immune restoration.

Additional literature searches on IRIS in HIV positive postpartum patients revealed two case reports in Uganda that described Cryptococcal meningitis and tuberculous meningitis as postpartum ART-related IRIS in one and eight mothers, respectively.^12,13

Diagnostic Classification of IRIS

To avoid over-attribution of disease to IRIS and address diagnostic uncertainty, each condition in our patient was independently evaluated. Conditions were categorized as shown below in Table 3.

Table 3.

Diagnostic Classification of IRIS

Condition	Revised interpretation	Discussion
Kaposi sarcoma	Confirmed unmasking IRIS	Evidence of immune recovery, diagnostic confirmation, temporal relationship to ART initiation
Oral/oesophageal candidiasis	Confirmed unmasking IRIS	Evidence of immune recovery, diagnostic confirmation, temporal relationship to ART initiation
Severe thrombocytopenia	Probable IRIS	Occurred during immune recovery demonstrating possible inflammatory phenomena but could have alternative explanations.
Severe anaemia	Probable IRIS	Occurred during immune recovery demonstrating possible inflammatory phenomena but could have alternative explanations.
Viral pneumonitis	Probable IRIS	Occurred during immune recovery demonstrating possible inflammatory phenomena but could have alternative explanations.
Hepatobiliary inflammatory syndrome	Probable IRIS	Occurred during immune recovery demonstrating possible inflammatory phenomena but could have alternative explanations.
Pulmonary embolism	Possible IRIS	Occurred within the timeframe for IRIS but also have recognized non-IRIS causes. They are therefore considered as possible IRIS
Peripartum cardiomyopathy	Possible IRIS	Occurred within the timeframe for IRIS but also have recognized non-IRIS causes. They are therefore considered as possible IRIS

Discussion

Herein is the initial description of an HIV positive post-partum woman who was initiated on HAART with a baseline CD4 count below 200cells/ul and developed a total of eight IRIS conditions three months postpartum - Oral candidiasis, Peripartum cardiomyopathy, severe anemia, severe thrombocytopenia, bilateral and extensive pulmonary embolisms, HIV-associated cholangitis, viral pneumonitis, and Kaposi’s sarcoma.

Ten cases, including this report, were identified as manifestations of multiple or many HIV-related IRIS. Seven of these cases displayed in Table 1 had three IRIS conditions,^3-5,7,9-11 while three of the cases, inclusive of this one, had six or more IRIS conditions.^6,8 Our patient, on the contrary, stands out because she experienced eight different IRIS manifestations, the highest documented IRIS conditions in a postpartum woman across six systems - gastrointestinal, cardiovascular, hematologic, pulmonary, hepatobiliary, and dermatologic systems.

Despite all ten patients having varying degrees of immune suppression, the common denominator in all cases was the fact that the patients’ CD4 counts were less than 200cells/ul, signifying advanced HIV disease with a total of 42 IRIS manifestations with the median time to first IRIS event was 21 days (IQR 13.5 to 55) (range: 4 to 105 days).

Initiation of HAART in our patient’s third trimester played a critical role in setting the foundation for unmasking IRIS, so much so that the intersection of the eight IRIS conditions created a complex clinical scenario of Oral candidiasis, Peripartum cardiomyopathy, severe anemia, severe thrombocytopenia, bilateral and extensive pulmonary embolisms, HIV-associated cholangitis, viral pneumonitis, and Kaposi’s sarcoma.

Our patient’s CD4+ T-cell count of 196 cells/μL, showing advanced immunosuppression, was profoundly compounded by her pregnancy, a state that is characterized by immunological changes that could have increased the risk and severity of immune reconstitution.^12,13 Additionally, our patient could have been predisposed to IRIS because she initially presented with elements of advanced HIV disease - viral pneumonitis, peripartum cardiomyopathy, oral candidiasis, and pulmonary embolism.

The explanation for several unmasking or paradoxical immune reconstitution syndromes in our patient is that they occurred because of her post-partum immune rebound after giving birth to her baby, as evidenced by the patient’s symptoms worsening after delivery.

An in-depth immunological explanation is that pregnancy alters the immune system by causing a reduction and elevation of T helper 1 (Th1) and T helper 2 (Th2) immune responses, respectively, which results in an increased risk of infections. Additionally, pregnancy involves multiple immune pathway modulations involving altered macrophage phenotypes, fluctuating cytokine profiles, regulatory T-cell expansion, changes in dendritic cell function that vary throughout gestation. This immunological situation is, however, reversed postpartum, leading to restoration of pro-inflammatory immune activity and increased cell-mediated immunity resulting in an immune rebound, which may result in IRIS from postpartum disease, ¹³ which was consistent with our patient.

What makes this case unique is that postpartum paradoxical exacerbation in HIV has been described before with single-disease entities – cryptococcal meningitis and tuberculous meningitis.^12,13 Our patient demonstrated a convergence of two immunological processes: ART-induced immune responses and postpartum immune restoration. And to the best of our knowledge, this is the first documented case of multiple disease manifestations in postpartum paradoxical exacerbation in HIV.

In reviewing the nine published cases, only three cases^6,8 inclusive of this one, had six or more IRIS manifestations. What makes our case exceptional is that it has the highest documented IRIS manifestations of eight in a female, in comparison to the other two cases that reported multiple IRIS manifestations, both of whom were males,^6,8 the median age being 27 years.

In spite of the fact that our case presented a therapeutic and clinical challenge, exhibiting IRIS across six systems, during puerperium, the patient recovered and was discharged and is doing well, maintaining 100% adherence to HAART.

Due to the complexity, distinctiveness, and severity of our case, we have identified a need to introduce a new term: “multiplex” and, in this particular regard, IRIS multiplex . This term will be used to classify cases with five or more IRIS conditions. The introduction of this term is intended to facilitate better recognition, early diagnosis, management, and comprehension of such patients and potential patients by healthcare professionals in the future.

Comparison With the Present Case

A comparison of the published literature reveals several unique features of our patient. Firstly, this case appears to be the first documented instance of a postpartum patient experiencing multiple concurrent inflammatory manifestations after ART initiation. Secondly, the coexistence of postpartum immune rebound and ART-induced immune restoration presents a unique immunological context. Thirdly, unlike previous reports, the present manuscript explicitly evaluates diagnoses and assigns diagnostic certainty for each IRIS manifestation. This cautious approach minimizes diagnostic inflation and aligns with reviewer recommendations.

Furthermore, while previous reports have described patients with multiple IRIS, none have examined the contribution of pregnancy-related immune modulation to multisystem inflammatory disease. Lastly, this case supports the concept that extensive IRIS exists on the clinical spectrum. Instead of introducing a definitive new classification, the manuscript proposes the descriptive term ‘IRIS multiplex’ as a hypothesis-generating concept for future investigation among patients who develop five or more concurrent or sequential IRIS manifestations.

Immune Reconstitution as the Central Pathophysiological Process

IRIS occurs when the immune system starts to recover after ART initiation. Some individuals may experience worsening symptoms due to an exaggerated inflammatory response triggered by their immune system reawakening in the presence of persistent microbial antigens, occult infections, or previously unrecognized inflammatory processes. The syndrome is therefore paradoxical: clinical deterioration occurs despite successful virological control and improving immune competence.

IRIS is a complex interplay of different types of immune cells. When the body restores its CD4+ T cells, other immune cells, like macrophages, dendritic cells, and natural killer cells, are also activated which can lead to an overproduction of inflammatory substances like interferon-γ, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-18 (IL-18), IL-1β, and chemokines such as CXCL10. These amplify tissue inflammation and can cause severe organ dysfunction even in the absence of ongoing infection.

One critical factor that plays a role in IRIS is the presence of antigens. People with advanced HIV often have subclinical opportunistic infections or neoplastic processes because of profound immunosuppression. Following ART initiation, immune restoration may cause inflammatory syndromes recognized clinically as unmasking IRIS. Alternatively, patients receiving treatment for known opportunistic infections may experience paradoxical clinical worsening despite improvement, indicating immune restoration rather than treatment failure.

Our patient had several risk factors for IRIS. She began ART while having advanced HIV, saw her CD4 count rise, and achieved full viral suppression. However, she began to demonstrate signs of IRIS shortly after starting ART. Notably, oral and esophageal candidiasis and Kaposi sarcoma only became evident once her immune system started to recover.

Postpartum Immune Rebound as a Potential Amplifier of IRIS

Another notable element in this case is how the timeframe of immune recovery after ART coincides with the changes in the immune system that happen after giving birth. While it’s often simplified to a shift from one type of immune response (Th1) to another (Th2), the reality is much more intricate, with various immune adjustments throughout the pregnancy.

Once the baby is born, this balance is disrupted. The removal of the placenta—a source of immune-modulating signals—leads to an increase in pro-inflammatory activity and a resurgence of cellular immunity. This rebound can aggravate autoimmune conditions and infectious diseases, including tuberculosis and cryptococcal meningitis. For women with HIV, particularly those starting ART late in their pregnancy, the postpartum period can trigger a combination of immune restoration from childbirth and immune recovery from ART.

This dual immune response could help explain why the patient experienced broad inflammatory reactions. About eight weeks after giving birth, she developed a multisystem inflammatory condition; this was a time when both the normal immune shifts after childbirth and the ART-aided immune recovery were likely at play. Though we can’t confirm exact mechanisms based on a single case, the overlap is plausible and aligns with previous accounts of postpartum worsening in other HIV-related infections.

Challenges in Diagnosis and Differentiating Conditions

One of the biggest hurdles in treating patients with advanced HIV is determining whether their worsening condition is due to true IRIS or other health issues. Many other conditions can mimic IRIS symptoms, including lingering infections, drug reactions, malignancies, and complications associated with pregnancy. Therefore, diagnosing IRIS requires a comprehensive approach, taking into account the clinical history, immune responses to ART, lab results, and imaging studies while ruling out other potential causes.

The reviewers of this case pointed out that some complications the patient experienced—like severe anemia, low platelet counts, pulmonary embolism, and peripartum cardiomyopathy—could potentially have other explanations outside of IRIS. We agree that we can’t definitively say these issues were caused by IRIS merely based on the timing of their occurrence. For example, severe anemia could stem from long-term HIV infection, nutritional issues, blood loss, or inflammation. Low platelet counts may arise due to a variety of factors, including the immune response itself or infections.

Pulmonary embolism is another complex issue, with many potential risk factors, including pregnancy and lack of movement—making it hard to attribute it to immune activity. Likewise, peripartum cardiomyopathy is a known complication that can happen in all women, not just those with HIV, so it shouldn’t be automatically linked to IRIS. That’s why we categorized these symptoms as possible IRIS manifestations, rather than confirmed ones.

On the other hand, oral and esophageal candidiasis and Kaposi sarcoma are strong indicators of unmasking IRIS since they appeared after ART began and coincided with clear immune recovery without other strong explanations. By separating confirmed, probable, and possible IRIS manifestations, we aim to paint a comprehensive picture that acknowledges both the evidence supporting IRIS and the uncertainties that remain.

Diagnostic Complexity and Differential Diagnosis

One of the principal challenges in managing patients with advanced HIV disease is distinguishing true IRIS from alternative causes of clinical deterioration. Conditions such as persistent opportunistic infection, antimicrobial resistance, drug toxicity, malignancy, autoimmune disease, pregnancy-related complications, and unrelated medical disorders may all mimic IRIS. Consequently, diagnosis remains fundamentally clinical and requires careful integration of temporal relationships, immunological response to ART, microbiological investigations, radiological findings, and exclusion of competing diagnoses.

The reviewers appropriately highlighted the possibility that several manifestations in this patient—including severe anaemia, thrombocytopenia, pulmonary embolism, and peripartum cardiomyopathy—might have explanations independent of immune reconstitution. We agree that these conditions cannot be attributed definitively to IRIS on the basis of temporal association alone. Severe anaemia may have resulted from chronic HIV infection, nutritional deficiencies, postpartum blood loss, bone marrow suppression, or inflammatory cytokine-mediated mechanisms. Similarly, thrombocytopenia may occur secondary to HIV-associated immune thrombocytopenia, medication effects, opportunistic infections, or immune reconstitution itself.

Pulmonary embolism represents another important diagnostic challenge. Pregnancy, the puerperium, HIV infection, prolonged hospitalization, systemic inflammation, and reduced mobility are all recognised prothrombotic risk factors. Whether immune activation directly contributed to thrombosis cannot be determined with certainty. Likewise, peripartum cardiomyopathy is a recognised pregnancy-related disorder that occurs in HIV-negative women and therefore should not automatically be regarded as an IRIS manifestation. For this reason, we classified these entities as possible rather than confirmed IRIS manifestations.

In contrast, oral and oesophageal candidiasis and Kaposi sarcoma fulfilled the strongest criteria for unmasking IRIS because they became clinically apparent after ART initiation, coincided with objective immune recovery, and lacked more convincing alternative explanations. By distinguishing confirmed, probable, and possible IRIS manifestations, we aim to provide a balanced interpretation that reflects both the strengths and the uncertainties of the available clinical evidence.

The Proposed “IRIS Multiplex” Concept

A central objective of this report was to explore whether patients developing numerous concurrent inflammatory manifestations after immune restoration represent a recognisable clinical phenotype.

Our structured literature review identified only a small number of published reports describing patients with three or more IRIS manifestations. Even among these reports, clinical presentations were heterogeneous, involving different pathogens, organ systems, and degrees of immunosuppression. Consequently, current evidence is insufficient to support creation of a formal diagnostic classification.

For this reason, we have intentionally revised our terminology in response to peer-review comments. Rather than introducing IRIS multiplex as a new disease entity or diagnostic category, we propose it as a descriptive, hypothesis-generating term that may facilitate recognition of exceptionally complex presentations characterised by multiple concurrent or sequential inflammatory manifestations following immune reconstitution.

Within this framework, the proposed term may be useful when the following features are present:

• 1. Documented HIV infection with recent initiation or re-initiation of ART.

• 2. Objective evidence of immune recovery.

• 3. Multiple inflammatory manifestations affecting several organ systems.

• 4. Careful exclusion of alternative diagnoses.

• 5. Recognition that individual manifestations may differ in their degree of diagnostic certainty.

Importantly, we do not propose that the number of inflammatory manifestations alone defines a new syndrome. Instead, we suggest that future observational cohorts may determine whether patients with extensive multisystem inflammatory disease represent a clinically distinct subgroup of IRIS with unique immunological mechanisms, prognostic implications, or management considerations.

Accordingly, the terminology should be interpreted as descriptive rather than prescriptive and should not replace established IRIS diagnostic criteria.

Limitations

Several limitations should be considered when interpreting this report. First, this is a single-patient case report and therefore cannot establish causality between immune reconstitution and every inflammatory manifestation observed. The temporal relationship between ART initiation and disease progression is suggestive but does not prove that all manifestations resulted directly from IRIS.

Second, several important laboratory investigations were unavailable because of financial and logistical constraints. Baseline HIV viral load before ART initiation, serial inflammatory biomarkers, cytokine profiling, Epstein–Barr virus PCR, cytomegalovirus PCR, herpes simplex virus PCR, and detailed thrombophilia investigations could not be performed. Consequently, alternative infectious or inflammatory mechanisms cannot be completely excluded.

Third, certain manifestations—including pulmonary embolism, severe anaemia, thrombocytopenia, hepatobiliary inflammation, and peripartum cardiomyopathy—have recognised non-IRIS causes. Although these events occurred within the expected temporal window for immune restoration, attribution to IRIS remains inferential. To address this uncertainty, the present manuscript classifies these manifestations according to their degree of diagnostic certainty rather than assigning definitive IRIS diagnoses.

Fourth, the structured literature review included only published English-language reports. Because multisystem IRIS is rare, publication bias is likely, and additional unpublished or non-English cases may exist. Furthermore, heterogeneity of case reports precluded quantitative synthesis or formal meta-analysis.

Finally, because prospective immunological studies were unavailable, the proposed relationship between postpartum immune rebound and extensive inflammatory disease remains hypothetical. Larger prospective studies incorporating immunophenotyping, cytokine profiling, and serial virological measurements will be required to clarify the biological mechanisms underlying these observations.

Conclusion

This report describes an HIV-positive woman who developed extensive multisystem inflammatory manifestations during the postpartum period following initiation of ART in late pregnancy. The combination of documented immune recovery, temporal association with ART initiation, exclusion of major competing opportunistic infections, and favourable clinical response following continued ART supports immune reconstitution as an important contributor to her clinical presentation and underscores the critical importance of closely monitoring HIV positive ART-naïve pregnant women with advanced immunosuppression commencing anti-retroviral therapy.

Nevertheless, not all inflammatory manifestations fulfilled equivalent levels of diagnostic certainty. By distinguishing confirmed, probable, and possible IRIS manifestations, this revised report provides a more balanced interpretation that recognises the complexity of multisystem disease in advanced HIV infection while avoiding diagnostic over-attribution.

Our findings further suggest that postpartum immune restoration, altered immunity due to pregnancy, post-partum immune rebound, and advanced immune suppression may amplify inflammatory responses during early ART, representing an under-recognised clinical phenomenon that deserves further investigation.

Finally, we propose “IRIS multiplex” as a descriptive, hypothesis-generating term for patients with extensive multisystem inflammatory manifestations during immune reconstitution. This terminology is intended solely to facilitate clinical recognition and stimulate future research rather than establish a new diagnostic classification. Prospective multicentre studies incorporating standardised diagnostic criteria and immunological investigations are needed to determine whether this proposed phenotype represents a distinct subset of IRIS.

ORCID iD

Christine Katusiime https://orcid.org/0000-0001-8791-7222

Ethical considerations

Not applicable Institutional ethical approval was not required for publication of this single-patient case report according to local institutional policy. The manuscript complies with the ethical principles outlined in the Declaration of Helsinki. Patient confidentiality has been maintained throughout the manuscript.

Consent for Publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying clinical information. The patient reviewed the purpose of publication and understood that although all reasonable efforts would be made to protect anonymity, complete anonymity cannot be guaranteed. All identifying information has been removed or anonymized in accordance with institutional and journal requirements. The authors confirm that the patient provided written informed consent before submission of the manuscript.

Data Availability Statement

Not applicable (this manuscript does not report data generation or analysis).*