HIV

A 70-Year-Old Woman with Cough and Shortness of Breath

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Presentation of Case

Dr. Alison C. Castle: A 70-year-old woman with advanced human immunodeficiency virus (HIV) infection was evaluated in a clinic in KwaZulu-Natal, South Africa, because of cough, shortness of breath, and malaise.

Fifteen years before the current presentation, the patient received a diagnosis of HIV infection after she had presented with substantial weight loss and fatigue. The initial CD4 cell count obtained at the time of diagnosis was 29 cells per microliter (reference range, 332 to 1642). Antiretroviral therapy (ART) with stavudine, lamivudine, and efavirenz was started. During the subsequent year, the symptoms resolved, the HIV RNA level became undetectable, and the patient reported adherence to her medications. Ten years before the current presentation, additional ART became accessible within South Africa, and the ART regimen was changed to tenofovir disoproxil fumarate, emtricitabine, and efavirenz.

Five years before the current presentation, the patient was admitted to a local hospital because of diarrhea and diffuse myalgias, and she was found to have virologic failure. The ART regimen was changed to zidovudine, lamivudine, and lopinavir–ritonavir. During the subsequent 4 years, the patient reported adherence to these medications without a lapse in treatment. The HIV RNA level ranged from 68 to 594,000 copies per milliliter of plasma (reference value, undetectable).

Twelve months before the current presentation, the patient had new shortness of breath, cough, anorexia, and weight loss. During the subsequent 4 weeks, the symptoms progressively increased in severity. When the shortness of breath worsened to the extent that she was unable to walk, she sought evaluation at the clinic. The temporal temperature was 36.8°C, the blood pressure 104/64 mm Hg, and the pulse 87 beats per minute. The body-mass index (the weight in kilograms divided by the square of the height in meters) was 16.9. On examination, the patient appeared ill but was able to speak in full sentences. Auscultation of the chest was limited because of frequent coughing; diffuse crackles were present in both lungs.Table 1.Laboratory Data.

Nucleic acid testing of a nasopharyngeal swab was positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Examination of an acid-fast bacilli smear of the sputum was positive for mycobacteria, and subsequent nucleic acid testing and culture of the sputum was positive for Mycobacterium tuberculosis. Other laboratory test results are shown in Table 1. In accordance with recommendations from the South African Department of Health, the patient was instructed to isolate at home and complete a course of treatment for tuberculosis, which included rifampin, isoniazid, pyrazinamide, and ethambutol.

During the subsequent 6 months, the patient took the antimycobacterial medications, and the shortness of breath and cough decreased but still persisted. Her weight decreased by 8 kg, even though the anorexia had resolved. Four months before the current presentation, new headaches and mouth ulcers developed, and the patient sought evaluation at the clinic. A sputum specimen was obtained for examination of an acid-fast bacilli smear and mycobacterial nucleic acid testing and culture, all of which were negative. The HIV RNA level was 151,000 copies per milliliter of plasma. The patient was scheduled for a follow-up appointment.

Twelve days before the current presentation, the patient presented to the clinic for follow-up, and the ART regimen was changed to tenofovir disoproxil fumarate, lamivudine, and dolutegravir. When the symptoms did not abate, the patient presented to the clinic for additional evaluation. She described persistent shortness of breath and dry cough, as well as headaches on the right side and mouth ulcers. The review of systems was notable for fatigue and weakness during the past 12 months, as well as fever, night sweats, chest pain, mouth ulcers, and odynophagia. She had no ageusia, anosmia, vision changes, abdominal pain, nausea, vomiting, diarrhea, rash, or joint pain. Radiography of the chest had not been performed.

The patient had not received vaccines for coronavirus disease 2019 (Covid-19). She took tenofovir disoproxil fumarate, lamivudine, and dolutegravir, as well as acetaminophen for muscle pain as needed. There were no known drug allergies. She did not smoke cigarettes, drink alcohol, or use illicit drugs; she did not take any remedies from traditional healers. The patient lived with her daughter in a rural farming community in a coastal region of South Africa, and she had not traveled recently. She commuted by foot within her community and had regular exposure to cattle, goats, chickens, and dogs. Her household water supply originated from a borehole and was untreated.

On examination, the patient was alert but appeared ill and cachectic. She coughed throughout the interview. The blood pressure was 97/71 mm Hg, the pulse 91 beats per minute, and the respiratory rate 20 breaths per minute. The body-mass index was 13.7. The mucous membranes were dry. She had thrush on the tongue, as well as superficial ulcers on the buccal mucosa. On auscultation of the chest, diffuse crackles were present in both lungs and were worst in the right lower lobe. The remainder of the physical examination was normal. The blood levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were normal. Other laboratory test results are shown in Table 1.

A diagnostic test was performed.

Differential Diagnosis

Dr. Rajesh T. Gandhi: I am aware of the final diagnosis in this case. This 70-year-old South African woman, who had advanced HIV infection and a recent history of Covid-19 and pulmonary tuberculosis, presented with dyspnea, cough, odynophagia, and headaches. On examination, she had oral candidiasis, oral ulcers, and pulmonary crackles. Laboratory studies were notable for pancytopenia, a low CD4 cell count (<10 cells per microliter), and a decrease in the HIV RNA level after a recent viral rebound. Radiographs were not available.

When formulating a differential diagnosis, I will first define the features of her underlying condition, including her recent infections and immunocompromised state. Then, I will identify potential causes of her initial respiratory symptoms. Ultimately, I will refine the differential diagnosis on the basis of subsequent features of her presentation, including the oral ulcers and headaches.

DEFINING THE FEATURES OF THE PATIENT’S UNDERLYING CONDITION

At the time of the diagnosis of HIV infection, the patient had had a CD4 cell count of 29 cells per microliter — the diagnosis in this patient, as in many patients, was delayed until she already had a low CD4 cell count.1-3 A delayed diagnosis of HIV infection puts patients at risk for many opportunistic infections and cancers, puts sexual partners at risk for HIV acquisition, and is associated with a higher risk of subsequent complications, most likely because of a “legacy effect” of immune dysregulation.4 In addition to advanced HIV infection, the patient had a recent history of SARS-CoV-2 infection. Studies suggest that persons with HIV infection have worse Covid-19 outcomes, particularly if they have a low CD4 cell count or a high HIV RNA level.5-8 The patient’s markedly immunocompromised state placed her at risk for persistent SARS-CoV-2 infection and subsequent fungal superinfection. Finally, she had a recent history of pulmonary tuberculosis, which also increases the risk of severe Covid-19 outcomes and fungal superinfection, perhaps because of lung damage.5

IDENTIFYING POTENTIAL CAUSES OF THE PATIENT’S INITIAL RESPIRATORY SYMPTOMS

In this patient with advanced HIV infection, potential causes of her initial respiratory symptoms include noninfectious complications, such as cancer and heart failure, as well as infectious causes of pneumonia.

Cancer

Advanced HIV infection is associated with several cancers, including non-Hodgkin’s lymphoma and human herpesvirus 8–associated cancers, such as Kaposi’s sarcoma. Kaposi’s sarcoma can involve the lungs but is an unlikely diagnosis in this patient for two reasons. First, there were no evident mucocutaneous lesions, unless the oral ulcers were sarcomatous lesions. Second, Kaposi’s sarcoma is less common in women than in men who have sex with men, owing to a difference in the prevalence of human herpesvirus 8.

HIV Cardiomyopathy

Advanced HIV infection is associated with dilated cardiomyopathy and heart failure.9 However, this diagnosis would not explain other features of this patient’s clinical presentation, such as the oral ulcers and headaches.

Bacterial Pneumonia

Bacterial pneumonia occurs frequently in persons with HIV infection and may be due to one of several common or uncommon organisms, such as Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Pseudomonas aeruginosa, Mycoplasma pneumoniae, or Chlamydia pneumoniae. This patient had been exposed to farm animals, which suggests the possibility of infection with rhodococcus species (after horse exposure) or C. psittaci (after exposure to pet birds or poultry). Exposure to goats and sheep suggests the possibility of infection with Coxiella burnetii, but the patient’s normal levels of alanine aminotransferase and aspartate aminotransferase make this diagnosis unlikely. Legionella can be found in borehole water, which she had ingested, but it is more common in manmade aquatic reservoirs.10 Nocardia may cause pneumonia and spread to the central nervous system; nocardiosis is a consideration, given her new headaches. However, this patient had had cough and dyspnea for several months, which makes most types of bacterial pneumonia unlikely because they tend to have a more acute presentation and progress over a shorter period of time.

Mycobacterial Pneumonia

Patients with M. tuberculosis infection and a low CD4 cell count can present with opacities in the middle or lower lobes, lymphadenopathy, and a miliary pattern on chest radiography. Drug-resistant M. tuberculosis infection would be a possibility if the patient had had incomplete adherence to her antimycobacterial medications. However, 4 months before the current presentation, follow-up mycobacterial nucleic acid testing of the sputum had been negative, which makes this diagnosis unlikely. M. avium complex usually causes disseminated infection, rather than pulmonary disease, in persons with advanced HIV infection.

Fungal Pneumonia

Pneumocystis jirovecii pneumonia is one of the most common opportunistic infections in persons with HIV infection. Patients with P. jirovecii pneumonia typically present with cough, dyspnea, fever, and hypoxemia, which is sometimes exertional. However, this diagnosis would not explain the patient’s oral ulcers or headaches.

Other potential fungal causes of pneumonia in persons in southern Africa with advanced HIV infection are Emergomyces africanus (formerly emmonsia species), cryptococcus, aspergillus, blastomyces, and histoplasma. E. africanus is the most common dimorphic fungus implicated in human disease in southern Africa and can cause pulmonary or disseminated infection in persons with HIV infection.11 Cryptococcal infection may lead to pneumonia and often results in meningitis, which could explain the headaches in this patient. However, a serum lateral flow assay for cryptococcal antigen was negative, which rules out cryptococcal meningitis, although not cryptococcal pneumonia. Aspergillus can cause pulmonary infection; risk factors for pulmonary aspergillosis in this patient include the low CD4 cell count, leukopenia, and recent history of Covid-19 and tuberculosis.

Parasitic Pneumonia

Potential parasitic causes of pneumonia in persons with advanced HIV infection include toxoplasma, strongyloides, cryptosporidium, and microsporidium. However, other features of this patient’s presentation, including the oral ulcers and headaches, would not be easily explained by infection with these parasites.

Viral Pneumonia

Influenza tends to be more severe in immunocompromised patients, including those with advanced HIV infection.12 Viral pneumonia can also be caused by respiratory syncytial virus, parainfluenza viruses, human metapneumovirus, cytomegalovirus (although rarely in persons with HIV infection), or SARS-CoV-2.

REFINING THE DIFFERENTIAL DIAGNOSIS

After the patient’s initial respiratory symptoms, odynophagia and mouth ulcers developed. In a patient with advanced HIV infection, potential causes of these symptoms include infection with aspergillus, histoplasma, candida, cytomegalovirus, herpes simplex virus, or SARS-CoV-2. Noninfectious possibilities include lymphoma and aphthous ulcers. Only some of these causes would also explain her respiratory symptoms, with aspergillus, histoplasma, and SARS-CoV-2 infections leading the list.

Headaches also developed late in this patient’s clinical course. Possible causes include a focal brain lesion (including brain abscess), bacterial or fungal sinusitis, and meningitis. Bacterial causes are somewhat less likely to be the sole explanation, given her protracted disease course. It is notable that fungal infections, including aspergillosis, have been reported to cause sinus disease and focal brain lesions in persons with advanced HIV infection.

Finally, is there an explanation for the progression of shortness of breath, cough, headache, and mouth ulcers after the initiation of effective ART? The patient’s worsening condition may be attributed to immune reconstitution inflammatory syndrome (IRIS). She had risk factors for IRIS: low CD4 cell counts, a high HIV RNA level, and the recent initiation of effective ART. Multiple opportunistic infections and cancers can worsen after the initiation of ART. A potential case of IRIS in the context of acquired immunodeficiency syndrome (AIDS) and Covid-19 has been reported.13

PUTTING IT ALL TOGETHER

How can we best explain this patient’s initial respiratory symptoms, followed by the development of odynophagia, mouth ulcers, and headaches? Given her markedly immunocompromised state, I am concerned about the possibility of persistent SARS-CoV-2 infection. Persistent SARS-CoV-2 infection has been reported in immunocompromised hosts, including those with advanced HIV infection.14 In several cases, other opportunistic conditions or superinfections were also present.

The persistence of SARS-CoV-2 infection in persons with advanced HIV infection may lead to the evolution of SARS-CoV-2 viral mutations. In an instructive report, a severely immunocompromised woman with HIV infection was positive for SARS-CoV-2 RNA for more than 210 days; during that time, the spike gene of the virus developed multiple mutations associated with immune evasion.15 The patient eventually cleared SARS-CoV-2 RNA after her HIV RNA level was suppressed with the use of ART.16 This case and others highlight the importance of identifying persons with HIV infection, treating them with ART, and prioritizing Covid-19 vaccination and treatment in this population.

In addition, persistent SARS-CoV-2 infection would place this patient at risk for a superinfection that might explain the new onset of headaches. Superinfections that can occur after Covid-19 include fungal infections, such as aspergillosis or mucormycosis, which can lead to pneumonia or rhino-orbital cerebral disease. The mechanisms that confer a predisposition to fungal superinfection in patients with Covid-19 are unclear, but such superinfection may in part be related to epithelial injury by SARS-CoV-2 leading to enhanced fungal binding to airways or impaired antifungal immunity from lymphopenia.17 This patient had additional risk factors for aspergillosis, including advanced HIV infection, leukopenia, and potential lung disease related to her recent tuberculosis.17-19

Given this patient’s profound immunodeficiency, I suspect that she has persistent SARS-CoV-2 infection, which may account for some aspects of her clinical presentation (fever, cough, dyspnea, and an abnormal lung examination). In the context of Covid-19 and a low CD4 cell count, pulmonary and cerebral aspergillus superinfection could be the cause of her respiratory symptoms and headaches. An additional evaluation, including SARS-CoV-2 testing as well as chest and head imaging, is warranted.

Dr. Rajesh T. Gandhi’s Diagnosis

Advanced human immunodeficiency virus infection, persistent severe acute respiratory syndrome coronavirus 2 infection, and pulmonary and cerebral aspergillus superinfection.

Diagnostic Testing

Figure 1.Results of RT-PCR Testing for SARS-CoV-2.

Dr. Tulio de Oliveira: A reverse-transcriptase polymerase-chain-reaction (RT-PCR) test of a nasopharyngeal specimen was positive for SARS-CoV-2. Two gene targets were detected (the N gene and ORF1ab targets), but the S gene target was not detected. The mean cycle threshold value was 18.3. Details of two additional positive SARS-CoV-2 RT-PCR tests were retrieved from laboratory records, the first from 11 months before presentation and the second from 3 months before presentation (Figure 1). No negative SARS-CoV-2 RT-PCR tests were documented between the positive tests.Figure 2.Phylogenetic Tree of SARS-CoV-2 Delta Sequences.

Repeated positive SARS-CoV-2 RT-PCR tests could reflect reinfections with different SARS-CoV-2 variants or persistent infection.20 Residual specimens from the current test and the test performed 3 months before presentation were retrieved for SARS-CoV-2 whole-genome sequencing; no stored specimen was available from the first test, performed 11 months before presentation. Results of phylogenetic analysis were consistent with persistent SARS-CoV-2 infection; both genomes were clustered together on a long branch within the delta clade (Figure 2).Figure 3.Mutations in the Spike Gene.

The genomes showed substantial evolution from the delta variant (B.1.617.2), with amino acid changes particularly concentrated in the spike gene. As compared with the sequence for the delta variant, the sequence from the patient 3 months before presentation had 14 additional mutations in the spike gene (13 substitutions and one deletion) (Figure 3). The sequence from the patient at the time of the current presentation showed 5 additional amino acid substitutions in the spike gene, as well as a new deletion in the N-terminal domain (67–79del) that was probably responsible for the S gene target failure. Furthermore, there was evidence of continued evolution at a key neutralizing antibody escape residue, from F486L to F486V. Taken together, the genomic data strongly pointed toward persistent SARS-CoV-2 infection with intrahost evolution.

Laboratory Diagnosis

Advanced human immunodeficiency virus infection and persistent severe acute respiratory syndrome coronavirus 2 infection.

Discussion of Management

Dr. Richard J. Lessells: Since late 2020, there have been multiple reports of persistent SARS-CoV-2 infection with intrahost evolution, usually in immunocompromised hosts. In South Africa, we have documented persistent infections in persons with advanced HIV infection.16,21 Suspected persistent infections can be identified from longitudinal follow-up of individual patients in clinical care or research studies, from active surveillance for suspected reinfections or persistent infections, or from targeted investigation of unusual sequences obtained during routine genomic surveillance.

There are no specific evidence-based management guidelines for persistent SARS-CoV-2 infection.22 Case reports of persistent infection have described treatment with antiviral agents, monoclonal antibodies, and convalescent plasma, often in combination, but the efficacy of any single or combination therapy for persistent infection has not yet been established.23,24 At the time of the patient’s current presentation, antiviral agents (remdesivir, molnupiravir, and nirmatrelvir–ritonavir) and monoclonal antibodies were either not yet approved or not available for use in the public health sector in South Africa. Anti–SARS-CoV-2 monoclonal antibodies are no longer active against circulating subvariants of the omicron variant (B.1.1.529).

Effective treatment of the underlying disease is an essential component of the management of persistent SARS-CoV-2 infection in immunocompromised patients. Limited evidence from case reports of persistent SARS-CoV-2 infection in patients with advanced HIV infection suggests that effective clearance of SARS-CoV-2 can occur after the commencement of effective ART and HIV suppression.16,21 Given the treatment history in this patient, the ART regimen was changed to a once-daily fixed-dose combination of tenofovir disoproxil fumarate, lamivudine, and dolutegravir just before the current presentation.

Follow-up

Dr. Nithendra Manickchund (Internal Medicine): Because no antiviral therapies for SARS-CoV-2 infection were available in South Africa at the time of the patient’s current presentation, the goal was to suppress HIV replication and reconstitute her immune system to resolve the Covid-19. Five weeks after the ART regimen was changed to a dolutegravir-based regimen, the patient began to have severe headaches on the right side, ptosis of the right eye, and an inability to move her right eye laterally. She presented to the clinic with these acute neurologic changes and was transferred to the hospital out of concern for IRIS. Computed tomography (CT) of the head, performed after the administration of intravenous contrast material, revealed a mass in the cavernous sinus with occlusion of the right internal carotid artery. Aspergillus fumigatus was isolated from two sputum specimens. On review of a second CT scan of the head, the mass was thought to be suggestive of aspergillosis, and treatment with intravenous amphotericin B was initiated.

RT-PCR testing of nasopharyngeal specimens for SARS-CoV-2 remained positive for the first 2 weeks of the hospitalization, but the infection had resolved by the third week. The patient neared HIV suppression at that time, with an HIV RNA level of 118 copies per milliliter of plasma, and had a modest improvement in the CD4 cell count. While awaiting biopsy for the intracranial mass, the patient died suddenly in the hospital. A postmortem examination was not performed.

Final Diagnosis

Advanced human immunodeficiency virus infection, persistent severe acute respiratory syndrome coronavirus 2 infection, and rhinocerebral aspergillus superinfection.

Monocytes May Be a Stable Reservoir of HIV

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In a new study using blood samples from men and women with HIV on long-term suppressive therapy, a team of researchers led by Johns Hopkins Medicine scientists reports new evidence that HIV genomes can be found in circulating white blood cells called monocytes.

Their research is published in Nature Microbiology, in a paper titled, “Monocyte-derived macrophages contain persistent latent HIV reservoirs.”

Monocytes are a type of white blood cell in your immune system. They turn into macrophage or dendritic cells when an invading germ or bacteria enters your body. The cells either kill the invader or alert other blood cells to help destroy it and prevent infection. The scientists found evidence that blood samples from people with HIV undergoing long-term, standard antiretroviral therapy contained monocytes that harbor stable HIV DNA capable of infecting neighboring cells.

“The development of persistent cellular reservoirs of latent human immunodeficiency virus (HIV) is a critical obstacle to viral eradication since viral rebound takes place once anti-retroviral therapy (ART) is interrupted,” wrote the researchers. “Previous studies show that HIV persists in myeloid cells (monocytes and macrophages) in blood and tissues in virologically suppressed people with HIV (vsPWH). However, how myeloid cells contribute to the size of the HIV reservoir and what impact they have on rebound after treatment interruption remain unclear. Here we report the development of a human monocyte-derived macrophage quantitative viral outgrowth assay (MDM-QVOA) and highly sensitive T cell detection assays to confirm purity.”

“We don’t know how critical these monocytes and macrophages are to the eradication of HIV, but our results suggest we should continue research efforts to understand their role in this disease,” said Janice Clements, PhD, professor of molecular and comparative pathobiology at the Johns Hopkins University School of Medicine.

Scientists have long known that HIV stashes its genome most often in a type of immune cell called a CD4+ T-cell.

“To eradicate HIV, the goal is to find biomarkers for cells that harbor the HIV genome and eliminate those cells,” said Rebecca Veenhuis, PhD, assistant professor of molecular and comparative pathobiology at the Johns Hopkins University School of Medicine.

To further study the role of monocytes and macrophages in circulating blood as HIV reservoirs, the Johns Hopkins-led team of scientists obtained blood samples between 2018 and 2022 from 10 men with HIV, all of them taking long-term, standard antiretroviral medications.

The researchers extracted blood cells from the samples and grew the cells in the laboratory. Typically, monocytes transform very quickly—within about three days—into macrophages, producing monocyte-derived macrophages.

All 10 men had detectable HIV DNA in their monocytes-turned-macrophages, but at levels 10 times lower than those found in the men’s CD4+ T cells, the well-established HIV reservoir.

The researchers then used an experimental assay to detect intact HIV genomes in monocytes.

The scientists used the assay on blood samples taken from another group of 30 people with HIV, also treated with standard antiretroviral therapy. The researchers found HIV DNA in the CD4+ T cells and in monocytes of all 30 participants.

The scientists were also able to isolate HIV produced by infected monocytes from half of the research participants. The virus extracted from these cells was able to infect CD4+ T cells.

Three of the participants had their blood examined several times over the four-year study period, and each time, the scientists found HIV DNA and infectious virus produced by their monocyte-derived macrophages. “These results suggest that monocytes may be a stable reservoir of HIV,” said Clements.

In further research, the Johns Hopkins research team plans to pinpoint the subset of monocytes found to harbor HIV DNA and the source of these infected cells.

Duesseldorf patient cured of HIV; third person in four decades to recover from the disease

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Scientists have successfully cured a third person of HIV. The man codenamed “the Duesseldorf patient” was cured of the life-threatening disease after receiving a stem cell transplant, which also treated his leukaemia. Previously, two other patients have been cured following the high-risk procedure. The patients in Berlin and London were also suffering from the two diseases. 

Details of the latest success story, a.k.a., the Duesseldorf patient, have been revealed in the journal Nature Medicine.

While the patient’s name was not released, the study revealed that he is 53 years old and was diagnosed with HIV in 2008. Three years later, he was then diagnosed with a life-threatening form of blood cancer called acute myeloid leukaemia.

As per the study, “this third case of HIV-1 cure” provides “valuable insights that will hopefully guide future cure strategies”.

In 2013, the Duesseldorf patient underwent a bone marrow transplant using stem cells from a female donor that had a rare mutation in her CCR5 gene. As per AFP, this gene mutation has been found to stop HIV from entering cells. 

The patient celebrated the 10-year anniversary of the transplant on Valentine’s day, where the donor was the “guest of honour”.

In a statement, he said that he was proud of his ” worldwide team of doctors who succeeded in curing me of HIV — and at the same time, of course, of leukaemia”.

The bone marrow transplant used in this case is a severe and dangerous operation. Hence, it is only suitable for some special cases or a small number of patients suffering from HIV and blood cancer. Another challenge in this treatment is locating a bone marrow donor with the rare gene mutation.

Black Seed Extract Controls HIV Naturally in Case Study

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Black Seed Extract 'Cures' HIV Patient Naturally

There are words you don’t use in medicine today, such as “cure.” But a remarkable case study in an HIV positive patient treated with black seed extract resulted in a sustained remission, indicating a safe, accessible and affordable alternative to highly toxic antiretroviral HIV drugs may already exist.

Nigella Sativa, also known as black seed, has been studied for a wide rage of health benefits, but not until recently was it discovered to hold promise against potentially lethal viral infections, including hepatitis C[i] and now HIV.

A remarkable case study published in December 2012 in the African Journal of Traditional, Complementary, and Alternative Medicine described an HIV patient who, after undergoing treatment with a black seed extract, experienced a complete recovery, with no detectable HIV virus or antibodies against HIV in their blood serum, both during and 24 months after the therapy ended.[ii]

This was a remarkable and unexpected observation, described by the researchers as follows:

“Nigella sativa had been documented to possess many therapeutic functions in medicine but the least expected is sero-reversion in HIV infection which is very rare despite extensive therapy with highly active anti-retroviral therapy (HAART). ” [emphasis added]

Despite its commonplace use as the standard of care for HIV treatment globally, anti-retroviral therapy remains highly controversial, in part because the adverse health effects of the drug class may outstrip those associated with the HIV infection itself. This is especially true in cases where the infection was treated “early,” having been discovered through routine blood work in asymptomatic and otherwise still healthy patients. Drug therapy can also produce selective pressure on the HIV virus to mutate and gain resistance, with the net effect being that a stronger, more drug-resistant form of HIV is produced in the body at the same time that the drugs have done severe and even irreversible damage to the patient’s immune system.  

Sadly, however, the decline and ultimate death of the patient is rarely if ever attributed to the treatment (and its many iatrogenic effects) but rather to the “disease” itself — a well-known problem in our failed “war against cancer” where the victim (patient) and the “cancer” gets blamed for the incessant failure and even disease-promoting properties of chemotherapy, radiation and surgery. 

This is all the more reason why the possibility that an ancient healing food like black seed — which the research shows is generally safe, affordable and accessible — can fight HIV is so exciting.

The ‘Miraculous’ Recovery

At the outset of the study, the patient presented with classical symptoms of symptomatic HIV infection, “with [a] history of chronic fever, diarrhoea, weight loss and multiple papular pruritic lesions of 3 months duration.” Examination identified moderate weight loss, with laboratory confirmed tests showing ‘sero-positivity’ to HIV infection with a “pre-treatment viral (HIV-RNA) load and CD4 count of 27,000 copies/ml and CD4 count of 250 cells/ mm(3) respectively.”

CD4 cells are essential for the adaptive immune response in the body against a wide range of opportunistic infections and is the primary target of HIV infection. CD4 cell count and status therefore represent a primary diagnostic marker for the severity of HIV infection and the patient’s prognosis.

The patient was administered a black seed concoction of 10 mls twice daily for 6 months, resulting in a rapid improvement in symptoms and significant reductions in viral load:

“Fever, diarrhoea and multiple pruritic lesions disappeared on 5th, 7th and 20th day respectively on Nigella sativa therapy. The CD4 count decreased to 160 cells/ mm3 despite significant reduction in viral load (≤1000 copies/ml) on 30th day on N. sativa.”

By the 187th day on black seed therapy, testing indicating the blood was entirely cleared of signs of infection, a so-called “sero-negative status.” The post-therapy CD4 counts increased from baseline to a normalized 650cells/ mm(3) with an undetectable viral (HIV-RNA) load.

Follow up tests revealed that even after 24 months without herbal therapy the patient’s HIV tests remained normal, without any indication of infection or associated immune suppression. They concluded:

 “This case report reflects the fact that there are possible therapeutic agents in Nigella sativa that may effectively control HIV infection.”

Black seed is only one plant ally in the vast array of natural compounds with experimentally confirmed anti-HIV properties. GreenMedInfo.com’s database contains research on natural substances capable of reducing antiretroviral drug toxicity, as well as that directly inhibit the replication of the HIV virus.

Patient achieves HIV and blood cancer remission three decades after HIV diagnosis through stem cell transplant at City of Hope

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  • Known as the City of Hope patient, he is the fourth patient in the world and the oldest to go into long-term remission of HIV without antiretroviral therapy (ART) for over a year after receiving stem cells from a donor with a rare genetic mutation. He is now 66 years old. He was 63 when he received the transplant. 
  • Among those patients, he also had HIV the longest, since 1988, before going into remission for HIV and leukemia.
  • Patient’s case opens up opportunities for older patients living with HIV and a blood cancer to receive a transplant and achieve remission for both diseases if a donor with rare genetic mutation can be identified.
  • Research presented today at AIDS 2022 press conference, highlighting the latest HIV research.
  • City of Hope is a global leader in stem cell transplantation for patients with blood cancers and patients with HIV/blood cancer.

LOS ANGELES — City of Hope, one of the largest cancer research and treatment organizations in the United States, announced today that a 66-year-old man who was diagnosed with HIV in 1988 has been in remission of the virus for over 17 months after stopping antiretroviral therapy (ART) for the disease following a stem cell transplant from an unrelated donor for leukemia, according to research presented today at the AIDS 2022 press conference by Jana K. Dickter, M.D., City of Hope associate clinical professor in the Division of Infectious Diseases. He received the transplant nearly 3 1/2 years ago at City of Hope. 

The man, known as the City of Hope patient, lived with HIV for over 31 years, the longest of any of the three previous patients with HIV who have gone into remission for a blood cancer and HIV. He was 63 years old when he received a transplant, the oldest patient to receive a transplant and go into remission for HIV and leukemia. 

The patient received a chemotherapy-based, reduced-intensity transplant regimen prior to his transplant that was developed by City of Hope and other transplant programs for treatment of older patients with blood cancers. Reduced-intensity chemotherapy makes the transplant more tolerable for older patients and reduces the potential for transplant-related complications from the procedure. 

The patient received a blood stem cell transplant at City of Hope in early 2019 for acute myelogenous leukemia from an unrelated donor who has a rare genetic mutation, homozygous CCR5 Delta 32. That mutation makes people who have it resistant to acquiring HIV. CCR5 is a receptor on CD4+ immune cells, and HIV uses that receptor to enter and attack the immune system. But the CCR5 mutation blocks that pathway, which stops HIV from replicating.

The City of Hope patient has not shown any evidence of having replicating HIV virus since the transplant. He stopped taking ART for HIV in March 2021. He might have been able to stop the therapies sooner but wanted to wait until he was vaccinated against COVID-19.

“We are proud to have played a part in helping the City of Hope patient reach remission for both HIV and leukemia. It is humbling to know that our pioneering science in bone marrow and stem cell transplants, along with our pursuit of the best precision medicine in cancer, has helped transform this patient’s life,” said Robert Stone, president and CEO of City of Hope and the Helen and Morgan Chu Chief Executive Officer Distinguished Chair. “The entire team at City of Hope is honored to make a difference every day in the lives of people with cancer, diabetes and other life-threatening diseases.” 

“We were thrilled to let him know that his HIV is in remission and he no longer needs to take antiretroviral therapy that he had been on for over 30 years,” Dickter said. “He saw many of his friends die from AIDS in the early days of the disease and faced so much stigma when he was diagnosed with HIV in 1988. But now, he can celebrate this medical milestone.”

“The City of Hope patient’s case, if the right donor can be identified, may open up the opportunity for more older patients living with HIV and blood cancers to receive a stem cell transplant and go into remission for both diseases,” Dickter added.

“When I was diagnosed with HIV in 1988, like many others, I thought it was a death sentence,” the man, who wishes not to be identified, said. “I never thought I would live to see the day that I no longer have HIV. City of Hope made that possible, and I am beyond grateful.”

City of Hope is a leader in treating patients with blood cancers, as well as patients with HIV and blood cancers with transplants. City of Hope has one of the nation’s leading transplant programs and is at the forefront of using transplants to treat older adults with blood cancers. The institution has performed nearly 18,000 transplants since 1976.

City of Hope was one of the first centers in the United States to perform effective, curative autologous transplants, which use a person’s own stem cells, for patients with HIV-related lymphoma. When many centers still treated patients with low-intensity, noncurative treatment approaches, City of Hope challenged that paradigm by demonstrating that autologous transplants could be used to cure patients with HIV-related lymphomas who would otherwise die.

City of Hope further pioneered the use of gene-modified blood stem cell transplants to evaluate the use of stem cells engineered to be resistant to HIV infection. The institution was also a primary national co-leader in two National Cancer Institute-sponsored trials for autologous as well as allogeneic stem cell transplantation, which use a donor’s stem cells, for patients with HIV and blood cancers. These trials led to a change to the national standards of care on how best to manage this vulnerable patient population.

Leveraging their expertise in cellular immunotherapy, City of Hope scientists have also developed chimeric antigen receptor (CAR) T cells that can target and kill HIV-infected cells and control HIV in preclinical research. They are working to start a clinical trial using CAR T cell therapy, which has the potential to provide HIV patients with a lifelong viral suppression without ART.

“The City of Hope patient is another major advancement. It demonstrates that research and clinical care developed and led at City of Hope are changing the meaning of an HIV diagnosis for patients across the United States and the world,” said John Zaia, M.D., Ph.D., director of City of Hope’s Center for Gene Therapy, Aaron D. Miller and Edith Miller Chair for Gene Therapy and a leader in HIV research. “City of Hope remains at the forefront of clinical research that changes people’s lives for the better.”

Under the care of City of Hope hematologist Ahmed Aribi, M.D., assistant professor in the Division of Leukemia, the patient received three different therapies to get him into remission before receiving a transplant. Most patients achieve remission after one therapy. The remission is necessary because a transplant is an intensive procedure that can cause serious complications.

For the transplant, Aribi and his team worked with City of Hope’s Unrelated Donor BMT Program — directed by Monzr M. Al Malki, M.D. — to find a donor who was a perfect match for the patient and had the rare genetic mutation, which is found in just 1-2% of the general population.

The patient did not experience serious medical issues after transplant.

“This patient had a high risk for relapsing from AML [acute myeloid leukemia], making his remission even more remarkable and highlighting how City of Hope provides excellent care treating complicated cases of AML and other blood cancers,” Aribi said. 

Source: City of Hope

Man is oldest person possibly cured of HIV after stem cell transplant

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A 66-year-old man is the oldest person yet to possibly be cured of HIV after undergoing a stem cell transplant, researchers announced Wednesday.

The man had HIV for more than 31 years when he received a blood stem cell transplant in early 2019 for acute myeloid leukemia (AML) using cells from a donor with a rare genetic mutation that prevents HIV from entering human cells, making people who have it resistant to most strains of the virus.

IDN0722Dickter_Graphic_01_WEB
Dickter J, et al.

The man has remained free of replicating HIV since his transplant — including for the last 17 months after stopping treatment for HIV, said Jana K. Dickter, MD, a physician at City of Hope National Medical Center in Duarte, California, where the patient was treated. His leukemia also is in remission.

“This research is particularly important because people with HIV continue to live longer thanks to advances in antiretroviral therapy,” Dickter said during a press conference announcing the findings ahead of the AIDS 2022 meeting in Montreal.

She said the case “opens possibilities for other older persons living with HIV and blood cancer to receive a transplant and achieve remission from both diseases if a donor with this rare genetic mutation can be identified.”

At 63 years old when he underwent the procedure, the “City of Hope patient” — as he is being called — was the oldest person with HIV and leukemia to undergo a transplant and go into remission for both, according to Dickter and colleagues.

He is at least the fourth person to have potentially been cured of HIV after receiving stem cells from someone with the CCR5-delta 32 mutation, and the second such case to be made public this year.

In February, researchers at the Conference on Retroviruses and Opportunistic Infections (CROI) announced that, for the first time, a woman had achieved sustained treatment-free remission this way. The so-called “New York patient” was said to be in remission for more than a year without treatment.

Two other cases were announced in past years at CROI, including the “Berlin patient,” later identified as Timothy Ray Brown, who died in 2020 following a recurrence of AML. Brown remained HIV free for the rest of his life after undergoing a bone marrow transplant in 2007.

A man known as the “London patient” who later identified himself as Adam Castillejo was reported in 2020 to have been in HIV remission for 30 months after undergoing allogeneic hematopoietic stem cell transplantation for Hodgkin’s lymphoma.

Experts have warned that stem cell transplantation is too risky and expensive to be a conventional cure for HIV. What these cases have done, however, is prove that it is possible to cure HIV, a complex virus that can be suppressed to undetectable levels with potent medication but remains notoriously difficult to eliminate, experts have said.

“Although a transplant is not an option for more people with HIV, these cases are still interesting, still inspiring, and help illuminate the search for a cure,” Sharon Lewin, MBBS, PhD, president-elect of the International AIDS Society and director of The Peter Doherty Institute for Infection and Immunity in Melbourne, Australia, said during an earlier press briefing. Lewis was not involved in the case.

Before his transplant, the “City of Hope” patient had sustained an undetectable viral load on ART since the 1990s, according to Dickter and colleagues. He had HIV the longest of any of the four patients who have achieved long-term HIV remission via stem cell transplant.

He also received the least immunosuppressive regimen of any of them before his transplant. The regimen was designed for older and less-fit patients “to make transplantation more tolerable for them,” Dickter said.

“This patient’s outcome and the results of this research are profound,” Dickter said. “Because this patient was older, lived the longest with HIV prior to transplant and received the least immunosuppressive therapy compared to the previous patients who had achieved remission from HIV after stem cell transplantation, we now have evidence that some HIV patients with blood cancers may not need fully intensive immunosuppressive therapy prior to transplant in order to put them into remission.”

The man continued taking an ART regimen of emtricitabine, tenofovir alafenamide and dolutegravir for more than 2 years after his transplant, stopping in March 2021 after he was vaccinated against COVID-19.

References:

Dickter J, et al. Abstract 12508. Presented at: International AIDS Conference; July 27-Aug. 2, 2022; Montreal (hybrid meeting).

Patient achieves HIV and blood cancer remission three decades after HIV diagnosis through stem cell transplant at City of Hope. https://www.cityofhope.org/patient-achieves-hiv-and-blood-cancer-remission-three-decades-after-hiv-diagnosis-through-stem-cell. Published July 27, 2022. Accessed July 27, 2022.

Perspective

Paul A. Volberding, MD)

Paul A. Volberding, MD

There have now been several cases of long-term HIV control following aggressive treatment of cancer diagnosed after HIV was suppressed by ART. Although the inability to detect HIV in these cases doesn’t prove that the infection has been truly cured, the longer these remissions are followed, the more likely a true sterilizing eradication or cure has been affected. Each of these cases is important, and we continue to hope that by studying them as a group, we might discover unifying evidence that enables us to find ways to the same end in larger numbers of cases without the toxicity and risk for mortality associated with cancer therapy and stem cell transplantation. The current case extends these previous reports and again used marrow donation from an individual carrying the delta CCR5-delta 32 mutation, which confers HIV infection resistance. We look forward to longer term follow-up of this case and of others that we hope to see over time. HIV cure remains a tremendous goal of a large and dedicated research community.

Paul A. Volberding, MD

Chief Medical Editor, Infectious Disease News

Professor emeritus of medicine

University of California, San Francisco

HIV an independent risk factor for nonalcoholic steatohepatitis

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A study of more than 1,300 women demonstrated that HIV is an independent risk factor for nonalcoholic steatohepatitis with significant nonalcoholic fatty liver disease activity and fibrosis, researchers reported.

“Nonalcoholic fatty liver disease (NAFLD) is common among people with and without HIV and is a leading cause of liver-related morbidity and mortality,” Jennifer C. Price, MD, PhD, associate professor of medicine at the University of California, San Francisco, told Healio. “However, most patients with NAFLD do not go on to develop cirrhosis.”

Women living with HIV faced a higher risk for nonalcoholic steatohepatitis with significant nonalcoholic fatty liver disease activity and fibrosis. Source: Adobe Stock.
Women living with HIV faced a higher risk for nonalcoholic steatohepatitis with significant nonalcoholic fatty liver disease activity and fibrosis.

According to Price, the FibroScan-AST (FAST) score can identify patients at risk for developing cirrhosis, or those with nonalcoholic steatohepatitis with an elevated NAFLD activity score and significant liver fibrosis.

“The advantage of the FAST score is that it does not require liver biopsy,” Price said. “We conducted this study to see if HIV was independently associated with higher risk of an elevated FAST score in a cohort of women with and without HIV.”

Jennifer C. Price, MD, PhD

Jennifer C. Price

Price and colleagues assessed 1,309 women without history of chronic viral hepatitis at 10 U.S. sites 928 with HIV and 381 who were HIV negative — and evaluated associations between HIV, demographic, lifestyle and metabolic factors with a FAST score higher than 0.35, which is considered elevated.

Women with HIV were more likely to have an elevated FAST score compared with those without HIV (6.3% vs 1.8%; P = .001). The researchers calculated that HIV infection was associated with 3.7-fold higher odds of elevated FAST score (P = .002), whereas a greater waist circumference was associated with 1.7-fold higher odds per each 10 cm (P < .001).

The study also showed that undetectable HIV RNA and current protease inhibitor use were independently associated with lower odds of elevated FAST score.

“HIV may increase the risk of more advanced NAFLD histology and liver disease progression,” Price said. “Unsuppressed HIV viral load and increased waist circumference are risk factors for elevated FAST in women, underscoring the importance of ART adherence and weight management in clinical practice.”

Cautious optimism for trials of mRNA-based HIV vaccine

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HIV IAVI lab

A scientist working in the design and development lab of the International AIDS Vaccine Initiative in 2011. Clinical trials for an mRNA vaccine against HIV have started Copyright: AIDSVaccine, (CC BY-NC-ND 2.0).

Speed read

  • Clinical trials for mRNA vaccine against HIV begin in United States
  • Upcoming trials in Rwanda and South Africa will test long-term suppression of HIV
  • But lack of license access and production capacity may hamper pan-African rollout

By: Inga Vesper

 

Scientists urge African leaders to demand fair licensing following clinical trials of an HIV vaccine candidate.

One remarkable thing about the COVID-19 pandemic was how quickly a vaccine was developed to combat the virus. A process that normally spans a decade or more — dozens of clinical trials, terse patent negotiations, complex roll-out strategies — was condensed into less than one year. mRNA, messenger ribonucleic acids that elicit an immune response from cells before degrading, provided a quick and safe solution to a global health threat.

mRNA technology has been under development since the 1960s, but its success in combatting coronavirus has resulted in renewed interest in using the technology for other diseases. One of these is another pandemic that has killed an estimated 36 million people since it was recognised in 1981 — human immunodeficiency virus, better known as HIV.

The United States’ National Institute of Allergy and Infectious Diseases (NIAID) announced in March the launch of a phase I clinical trial evaluating three experimental HIV vaccines based on an mRNA platform. NIAID director Anthony Fauci said that while finding an HIV vaccine had proven “a daunting scientific challenge”, there was now “an exciting opportunity to learn whether mRNA technology can achieve similar results against HIV infection.”

Elsewhere in the US, the first human trial of an mRNA vaccine against HIV launched in January this year. The vaccine candidate, developed with pharmaceutical company Moderna, is being administered to 56 HIV-negative adults in Washington, Atlanta, Seattle and San Antonio.

The HIV virus is a much more complex target for mRNAs, says Dagna Laufer, vice president of clinical trial development at the International AIDS Vaccine Initiative (IAVI), which is sponsoring the trial — dubbed IAVI G002.*

“If shown to have an acceptable safety profile and able to induce the desired immune response, the vaccine candidates could be the first stage of a multi-step vaccine regimen,” she says. “But we will need to undertake multiple trials to achieve this goal, and these trials will be conducted over at least a five- to ten-year period.”

What makes HIV such a difficult disease to tackle is that it is a retrovirus, meaning it stays in the body forever by copying its genome and inserting it into the host’s cells. This is unlike COVID-19, which is an RNA virus that is shed by the body after a few weeks. To protect against HIV, the mRNA vaccine must do more than just elicit a temporary immune response; it must encourage the body to produce a special type of B-cells — broadly neutralising antibodies — that can suppress HIV long-term.

Achieving this is incredibly tricky, not least because the message protein that can do this has not yet been conclusively identified. But non-mRNA vaccines for HIV are also struggling to take off. A trial for a non-mRNA vaccine developed by pharmaceutical company Johnson & Johnson was abandoned in 2021 after it emerged that the vaccine candidate provided about 25 per cent protection against HIV — a level considered too low to be effective.

Still, IAVI and Moderna are planning for success. A seperate trial on macaques in 2021 showed that their HIV vaccine candidate delivered a message that caused the monkeys to make antibodies that could neutralise an HIV infection. The next IAVI-funded trial, IAVI G003, is scheduled to start by mid-2022 and will be conducted at clinical research centres in Rwanda and South Africa, Laufer tells SciDev.Net. The idea behind the phase I trial is that African scientists will play “a leadership role” both in conducting the study and analysing the resulting data.*

Global South production

The shift of the trial to Africa may go some way towards addressing another major issue with vaccine trials for HIV — the lack of involvement of those most affected by the virus.

According to the World Health Organization, more than two-thirds of the 25 million people living with HIV live in Africa, where the risk of dying from the disease is also the highest.

There are a number of reasons for this: a lack of access to quality healthcare, the cost of antiretroviral therapy, and the stigma associated with HIV. These factors combine to make Africa a less interesting target for pharmaceutical companies.

This has been evident during the COVID-19 pandemic. Despite being home to 1.3 billion people, only 375 million vaccine doses had been administered in Africa as of March this year, according to the WHO.

For this reason, there is growing concern about access among those monitoring the development of mRNA and conventional vaccines for HIV. There is no certainty whether, if successful, an mRNA HIV vaccine will be available to those who need it most.

“Even if we do get an HIV vaccine, we have to do better than COVID-19 in terms of equity and access,” says Mitchell Warren, the executive director of AVAC, a global advocacy group for HIV prevention.

Warren says that conducting clinical trials in Africa is a good first step, but that this needs to be followed up with true collaboration. “Africa is not just a clinical trial site, Africa is a continent of [more than] 50 countries with leading researchers, with vaccine manufacturing capacity, with growing regulatory expertise,” he told SciDev.Net.

“If African partners are hosting clinical trials, they should also demand immediate access and registration of the final product. We do not want the research to be done there for a license elsewhere.”

Laufer says the IAVI G002 trial is “not yet on a product development pathway”. But issues around who gets to produce the vaccine, should it be successful, were highlighted with COVID-19. Moderna did not share the formula for its COVID-19 vaccine, but it has pledged not to enforce patents against companies manufacturing COVID-19 vaccines for 92 low- and middle-income countries. Other vaccine developers such as Pfizer and AstraZeneca also retained the patent information on how to make their vaccines. In response, the WHO and a South African consortium set up an mRNA technology transfer hub to create their own vaccines.

“Moderna has not proven itself to be generous when releasing the patent or making their COVID-19 mRNA vaccine available in developing countries to date,” says Monica Gandhi, the director of the University of California San Francisco Center for AIDS Research. “Therefore, we will need government and community pressure on the company to share its technology with the rest of the world, given that HIV incidence is highest in developing countries.”

Moderna did not respond to a request for comment from SciDev.Net. However, the company revealed plans in March to open an mRNA vaccine production facility in Kenya, which would manufacture the COVID-19 vaccine, among others. The company will make an initial US$500 million investment in the facility, but did not confirm whether some of this money would go towards work on the HIV vaccine.

For Warren, the Moderna announcement is good news because, he says, it will increase production capacity in the global South and diversify vaccine manufacturing. Having a product made within the region could also go some way towards alleviating vaccine hesitancy in Africa, where people have reported reluctance to accept COVID-19 vaccines due to a mistrust of global corporations.

“Any centralised corporate control of the mRNA platforms really feeds inequity,” Warren says. “We need distributed manufacturing. For a global pandemic you cannot rely on a single manufacturer.”

Study uncovers high rate of subclinical TB among people with HIV

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The incidence of subclinical tuberculosis among people with HIV in a South African study was similar to the incidence of clinical TB, suggesting that guidelines recommending symptom-based screening may need to be updated, researchers said.

“Globally, TB mortality remains unacceptably high with 1.4 million deaths each year. WHO’s ambitious End TB strategy focuses on early TB diagnosis and treatment of symptomatic individuals to achieve a 90% reduction in TB incidence by 2035,” Kogieleum Naidoo, MBChB, PhD, clinical head of the HIV and TB treatment research program at the Centre for the AIDS Programme of Research in South Africa (CAPRISA), and colleagues wrote.

Source: Adobe Stock.
Undiagnosed asymptomatic subclinical tuberculosis accounts for a substantial proportion of cases among people living with HIV/AIDS. Source:

They said undiagnosed asymptomatic subclinical TB “remains a significant threat to global TB control and accounts for a substantial proportion of cases among people living with HIV/AIDS.”

Naidoo and colleagues enrolled 402 adults with HIV who were previously treated for TB in the CAPRISA TRuTH study and screened them for TB over 36 months while they received HIV services, including ART. They used the data to estimate the incidence rates of TB.

Of the 402 adults, 48 (11.9%) had bacteriologically confirmed incident recurrent TB, including 17 (35.4%) with subclinical TB and 31 (64.5%) with clinical TB. The study showed that age, sex and BMI were similar among participants with subclinical, clinical and no TB.

According to Naidoo and colleagues, the incidence rates of recurrent TB overall, clinical TB and subclinical TB were 2.3 (95% CI, 1.7-3), 1.5 (95% CI, 1.1-2.2) and 0.9 (95% CI, 0.5-1.4) per 100 person-years, respectively.

In the subclinical TB group, 14 (82.4%) of the patients were diagnosed by TB culture only, 11 (64.7%) received TB treatment and six (35.3%) resolved TB spontaneously.

“Our study highlights the cyclical nature of TB disease progression and need for reconsideration of current TB screening and testing guidelines,” the authors wrote. “The challenge of using TB symptoms alone for finding and treating TB cases is demonstrated, emphasizing the importance of targeted universal TB screening, and testing among high-risk groups.”

Hemophagocytic lymphohistiocytosis: a rare disease unveiling the diagnosis of EBV-related large B cell lymphoma in a patient with HIV

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Abstract

Background

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease resulting from the overactivation of the immune system due to under regulation of cytotoxic lymphocytes, macrophages and natural killer (NK) cells. HLH is associated with malignancies, infections, autoimmune disorders and rarely AIDS and is rapidly fatal.

Case presentation

This case report identified a 53 year old male with acquired immunodeficiency syndrome (AIDS) who presented with neutropenic fever of unknown origin. He had two previous hospitalizations prior to the hospitalization diagnosing HLH. The first led to a diagnosis of drug fevers in the setting of treatment for thrombotic thrombocytopenic purpura and subsequent hospitalization led to empiric treatment of hospital acquired pneumonia after workup for intermittent fevers was negative. He was discharged but readmitted 10 days after for recurrence of neutropenic fevers. During this final hospitalization, he was found to have elevated liver enzymes, ferritin, triglycerides and soluble IL-2 receptor with persistent fevers, new splenomegaly and bicytopenia meeting the 2004 HLH criteria. Bone marrow biopsy confirmed the diagnosis of HLH as well as EBV associated large B-cell lymphoma. The patient improved on treatment with steroids, rituximab, tocilizumab, and chemotherapy but ultimately passed away due to refractory septic shock from multi-drug resistant Klebsiella pneumoniae.

Conclusion

This novel case highlights a patient diagnosed with HLH in the setting of several risk factors for the disease, including AIDS, B-cell lymphoma and EBV. Additionally, this case highlights the importance of early consideration of HLH in the setting of neutropenic fever without clear infectious etiology and search for malignancy associated reasons for HLH especially in immunocompromised patients.

Background

Hemophagocytic lymphohistiocytosis (HLH) is an aggressive, rapidly fatal, and often misdiagnosed hyper-activation of the immune system that can be seen in a variety of malignancies, infections, autoimmune disorders, and rarely HIV [1, 2]. This pathology results in excessive production of cytokines which in turn results in cellular destruction and eventual organ failure [3]. We present the case of a 53-year-old male with HIV/AIDS who was admitted with neutropenic fever in the setting of bone marrow failure, which preceded a diagnosis of HLH from EBV related Large B Cell Lymphoma.

Case presentation

A 53-year-old African-American male with a past medical history of HIV with CD4 count of 27 and undetectable viral load, hypertension, hyperlipidemia, colitis status post hemicolectomy, polysubstance abuse who presented with fever of unknown origin. Notably, the patient has had two prior admissions three months before this presentation. On his first admission, he was diagnosed with thrombotic thrombocytopenic purpura, responsive to Caplacizumab and prednisone. His hospital course was complicated by intermittent persistent fevers, which was eventually attributed to drug fever. There was consideration of DRESS syndrome during this admission although the patient did not have eosinophilia, which one study suggests is present in 97% of patients with DRESS syndrome [4]. Patient was discharged home but readmitted two weeks later with failure to thrive and was found to have neutropenic fevers of unknown origin. He underwent extensive workup for infectious etiology. CT chest showed persistent stable pulmonary nodules for which bronchoscopy was performed with lavage cytopathology significant only for colonized rare candida spp. He was found to have Epstein–Barr virus viremia. However, with no clear source he was treated empirically for hospital acquired pneumonia. He was discharged after resolution of his fevers to subacute rehab.

Ten days after discharge, he was readmitted for recurrence of neutropenic fevers, with absolute neutrophil count 532. Extensive workup revealed persistent fevers, splenomegaly, bicytopenia, elevated LFTs, ferritin, triglycerides, and soluble IL-2 receptor, meeting the 2004 hemophagocytic lymphohistiocytosis (HLH) criteria [5] (Tables 1, 2). Lymph node biopsy confirmed the diagnosis of EBV associated lymphoma (Fig. 1a–e). Bone marrow biopsy confirmed the diagnosis of immunodeficiency associated large B-cell lymphoma with EBV associated HLH (Fig. 2a–d). Patient was treated with a combination of steroids, rituximab, tocilizumab, and chemotherapy. Initially, the patient’s status improved but unfortunately the patient ultimately expired 5 days after intensive care unit (ICU) downgrade due to refractory septic shock secondary to multidrug resistant Klebsiella pneumoniae.Table 1  Diagnostic evaluation of the patient based on 2004 HLH criteria

Discussion

HLH is a rare disease associated with overactivation of the immune system, specifically the under regulation of cytotoxic lymphocytes, macrophages and natural killer (NK) cells. While primarily a pediatric entity, cases have been diagnosed in adults, with a predisposition for males, mean age range of 41–67 years, and an estimated incidence rate of 1 per 800,000 people [6, 7]. Etiology is poorly defined but associated with genetic abnormalities specifically impairing perforins (a key delivery molecule for proapoptotic granzymes) [8], especially in the pediatric population. HLH associated with genetic causes is termed primary HLH. Our patient unfortunately cannot be excluded from the diagnosis of primary HLH as genetic causes were not tested during his admission. Nonetheless, our patient had multiple associations to make the likely diagnosis of secondary HLH.

In adults, a 2015 single center study found the etiology of secondary HLH was commonly due to infection (41.1%), followed by malignancies (28.8%). Of the infectious etiologies, HIV and EBV both were the most common causes (5/30 and 5/30) [2]. Viral load of EBV quantified by PCR correlates with disease severity [6]. Interestingly, in our patient, his EBV viral load from previous admission was 38,000. As he further deteriorated and the diagnosis of HLH became clearer, his viral load increased to 97,900 (Table 1). Of the malignancy related causes, B-cell lymphoma was the most common, with 10 out of 21 patients [2]. It is likely that the disease driving the patient’s presentation was a combination of EBV, HIV and large B cell lymphoma.

In our patient, the diagnosis of lymphoma was made on lymph node biopsy (Fig. 1a–e) prior to the pathological diagnosis of HLH seen on bone marrow biopsy (Fig. 2a–d). This diagnosis of lymphoma was EBV-related as evidenced by the positivity of EBER in-situ hybridization on lymph node and bone marrow biopsy. To our knowledge, there have been no retrospective or prospective studies defining the incidence of HLH with underlying HIV, EBV, and B cell lymphoma. We found one case report describing a similar patient presentation [9]. Although NK function and genetics were not performed on our patient, our patient had clear triggers for HLH secondary to immune activation, rather than underlying genetic defects in lymphocytes, thus classifying his case under HLH disease rather than syndrome. Regardless, without treatment, HLH has a high mortality due to multiorgan failure.

According to the HLH-2004 trial, which determined the diagnostic criteria for HLH, histological identification of HLH was not required to make a definitive diagnosis. Nonetheless, in patients with clinical suspicion for HLH, bone marrow biopsy to search for hemophagocytosis or underlying malignancy could help aid in the diagnosis [10]. Further complicating the picture, the presence of hemophagocytosis in bone marrow biopsies was neither sensitive nor specific for the diagnosis of HLH. On the admission preceding the admission ultimately diagnosing HLH, our patient had a bone marrow biopsy that was negative for hemophagocytosis. This leads us to question whether bone marrow biopsy should be performed on all patients suspected of HLH [9]. According to a retrospective analysis of HLH confirmed patients, bone marrow biopsy only showed hemophagocytosis in 70% of patients [11]. In our case, bone marrow biopsy showed hemophagocytosis (Fig. 3) while also distinguishing the underlying etiology of HLH (Fig. 2a–d). Our patient case highlights the importance of early consideration of HLH in the setting of neutropenic fever without clear infectious etiology. Additionally, this highlights the importance of identifying the etiology of secondary HLH, including malignancy.

figure 1
Fig. 1
figure 2
Fig. 2
figure 3
Fig. 3

Abbreviations

HLH:

Hemophagocytic lymphohistiocytosisEBV:

Ebstein–Barr virusHIV:

Human immunodeficiency virusAIDS:

Acquired immunodeficiency syndrome

Source: springer.com