What Came First: Malnutrition or Severe Disease?

A 20-year-old female with depression presented to the emergency department (ED) with chronic weakness, fatigue, and 2 weeks of cough. Her cough was worsening in frequency and production. She denied hemoptysis, chest pain, difficulty breathing, or pain with inspiration. She reported a 50-pound unintentional weight loss over the last 2 years. She was prescribed mirtazapine for depression and appetite stimulation and protein shakes to supplement her nutrition. One year prior she was referred to a gastroenterologist for pancreatic edema on a computed tomography (CT) scan of the abdomen and pelvis. Further investigation including tissue transglutaminase IgA, fecal elastase, and a barium swallow were normal. She ate regularly and wanted to gain weight but avoided high-fat foods in favor of fruits, vegetables, beans, and tortillas. Additional chronic symptoms included hair loss, lower extremity rash, dizziness, and palpitations after eating. She denied fevers, night sweats, shortness of breath, discomfort while lying supine, nausea, vomiting, diarrhea, constipation, arthralgias, or bone pain.

Upon arrival to the ED, she had a temperature of 36.8C, heart rate of 62 beats per minute, blood pressure of 84/69 mmHg, respiratory rate 16, and SpO₂ 100%. Her weight was 22.2 kg (49 lbs) and BMI was 10.3 kg/m².

She was markedly cachectic (Fig 1A), but nontoxic in appearance and in no acute distress. Her cardiovascular examination revealed a regular rhythm without a murmur or rub on auscultation. Her breath sounds were diminished in the upper lobes bilaterally. A skin examination showed diffuse hair loss, skin breakdown, and peeling with a tender, erythematous, papular rash over the bilateral ankles, and nonpitting edema consistent with stasis dermatitis (Fig 1B).

Complete blood count and differential showed mild anemia and a normal peripheral white blood cell (WBC) count with a neutrophil predominance (Table 1). Other than a markedly low prealbumin, her chemistry and thyroid studies were normal (Table 2). HIV Type 1 and 2 polymerase chain reaction (PCR) were negative.

A chest radiograph (CXR) revealed a right upper lobe opacity and lucent lesions in the left proximal humerus (Fig 2). A focused assessment with sonography for trauma examination was performed, which showed a large pericardial effusion. Chest CT revealed the right upper lobe opacity with associated cavitation (Fig 3).

Dr Cohen, what qualified this patient for inpatient workup and management rather than continuing to be treated as an outpatient?

As for many conditions, admission criteria for malnourished children and adolescents vary depending on a variety of factors besides acuity of illness, such as diagnostic uncertainty, prior outpatient workup, prior ER visits, and the need for diagnostic testing.¹  Additional considerations include the risk of refeeding syndrome, the level of suspicion for a serious underlying cause such as malignancy, concern for abuse or neglect, and the need for a strict calorie count as a diagnostic test to distinguish organic causes from disordered eating.

Our patient had a concerning story for a serious organic etiology, as evidenced by her progressive course, lack of weight gain with caloric supplementation, and worsening pulmonary symptoms.

Dr Hergenroeder, what are the admission criteria for patients with an eating disorder? What is your differential diagnosis for her weight loss?

Criteria for inpatient admission for patients with eating disorders include ≤75% median BMI for age and sex, dehydration, electrolyte abnormalities, electrocardiogram abnormality, pulse < 50 beats per minute, temperature < 35.6C, hypotension (<90/45 mmHg), orthostatic instability, arrested growth and development, outpatient treatment failure, acute food refusal, uncontrollable bingeing or purging, an acute medical complication of malnutrition, or comorbid psychiatric or medical condition that prevents appropriate outpatient treatment.^2–4 

Though she met many of the above criteria for admission, most notably her BMI of 47.3% median for age and sex (Z-score ≪ −3), the diagnosis of an eating disorder was unclear. She desired to gain weight and her weight loss and restrictive eating pattern began with the loss of her grandfather 2 years before her presentation; thus, it may have been secondary to major depressive disorder.

After evaluation in the ED, she was admitted to Pediatric Hospital Medicine (PHM) and placed in a negative pressure room. PHM delayed beginning antibiotics and consulted the Infectious Disease team. Adolescent Medicine was consulted for the management of her severe malnutrition. An electrocardiogram showed low voltage QRS complexes (Fig 4). An echocardiogram showed normal biventricular function and redemonstrated the pericardial effusion without tamponade physiology. Because of concern for clinical instability, continued hypotension, and worsening electrolyte disturbances, including potassium 3.3 mEq/L, phosphorus 1.5 mg/dL, and calcium 7.6 mg/dL, she was transferred on the day of admission to the PICU for management of refeeding syndrome and closer monitoring.

Dr Hergenroeder, What is the Pathophysiology and Management of Refeeding Syndrome?

Refeeding syndrome is a clinical diagnosis characterized by electrolyte and metabolic disturbances typically beginning 1 to 3 days after initiating feeding.^5,6  With the onset of feeding, serum glucose increases, causing an increase in insulin secretion. Insulin causes movement of glucose, potassium, phosphate, calcium, and magnesium into the intracellular space, depleting these from the intravascular space; thus, baseline low levels of phosphate, potassium, or magnesium also increase the risk of developing refeeding syndrome.⁵ 

The challenge in correcting severe malnutrition is providing the patient with the necessary nutrition to recover without providing it too quickly. If the insulin response and subsequent shifts from the serum into the intracellular space are too robust, the decline in intravascular levels of these electrolytes leads to arrhythmias and potentially death. Thus, it is imperative to begin with strict limitations on nutrition.

Though adolescents require 35 to 45 kcal/kg per day to maintain healthy growth,⁷  severely malnourished patients start with 20 to 40 kcal/kg per day of nutrition to reach a goal weight gain of 100 to 300 g per day. The frequency of electrolyte monitoring depends on the patient’s baseline laboratories and degree of malnutrition.

On review of her medical record, our patient had lost a total of 77 pounds in 2 years, and she had a baseline low-normal phosphate of 2.1, placing her at high risk for refeeding syndrome. Formula was administered via a nasogastric to provide 25 kcal/kg per day, 30% of her daily caloric needs, with the rest comprised of a regular oral diet. Electrolyte supplementation and thiamine were also provided. On hospital day 9 her electrolytes stabilized, and she was transferred back to PHM for continued management. Her NG tube feeds were increased steadily until she was able to tolerate a full diet.

The Pediatric Infectious Diseases (ID) team was consulted to assist with the workup and management of presumed Mycobacterium tuberculosis (TB) pulmonary disease versus alternative infectious causes of cavitary pneumonia in the setting of severe malnutrition. TB risk factor screening revealed that she was born in Guerrero, Mexico, had immigrated to the United States when she was 10 years old, and had no known TB contacts.

Dr Cameron, What is the Workup for a Patient Presenting With Cavitary Pneumonia?

In working up a patient with a cavitary pneumonia, one must first consider the immune status of the host. Immunosuppressed patients are at increased risk of multifocal pneumonia with cavitation and rapid progression of disease with atypical pathogens, including TB, nontuberculous mycobacteria species (NTM), Actinomyces spp, Nocardia spp, fungal organisms, etc. Second, one must consider the laterality of pneumonia as right-sided lesions are more common with aspiration events. Third, the patient’s time course and clinical appearance at presentation offers clues to the etiology. A patient who experiences a rapid development of symptoms and is toxic appearing is more likely to have acute bacterial pneumonia, commonly caused by Staphylococcus aureus, Streptococcal spp (including S. pneumoniae and S. pyogenes), oral anaerobes, etc.⁸  In those with a more indolent clinical course, atypical pathogens should be considered. Lastly, the age of the patient matters as cavitary pneumonia is more common in infants and adolescents than in school-aged children.

A complete blood count with differential is useful as acute bacterial processes often have a leukocytosis with a left-shift. Thrombocytosis suggests inflammation and anemia supports an acute bleed in the cavity or chronic inflammation. Elevated c-reactive protein supports an acute process and erythrocyte sedimentation rate is often normal or only slightly elevated early on in infection, increasing as the infection progresses. Both values are often monitored over time and usually improve with medical or surgical treatment.

Depending on the patient population and risk factors, testing for TB infection or fungal pathogens is appropriate. In adolescents with TB risk factors, tests include an interferon-γ release assay testing (IGRA) and a tuberculin skin test (TST). A fungal blood culture, fungal biomarkers ([1,3]-β-D-glucan assay or Aspergillus galactomannan), Aspergillus Ab, Histoplasma Ab, Coccidioides Ab, Blastomyces Ab, and blood and urine Histoplasma antigen testing are appropriate for immunocompromised patients and those living in endemic regions.

Induced sputum can be collected and sent for bacterial, fungal, and mycobacterial cultures. For children who are unable to expectorate, a respiratory therapist can assist by administering inhaled saline to improve the sample, or one can perform early morning gastric aspirates.^9–11  In rare cases of easy accessibility or treatment failure, one can obtain cultures from an abscess collection. Our patient’s sputum was sent for routine bacterial cultures, an acid-fast bacilli (AFB) smear and culture, M.TB (Mycobacterium tuberculosis) PCR, fungal culture, and testing for endemic mycoses.

Radiologic evaluation requires anterior or posterior and lateral CXR, which may be followed by computed tomography scan of the chest with contrast as in this patient.

Though not routinely recommended, the ID team suggested performing a T-SPOT.TB, Quantiferon Gold-in-Tube (QFT), and a TST to increase the diagnostic sensitivity.^12–15  Sputum culture was smear positive for AFB, so the ID team recommended beginning rifampin, isoniazid, pyridoxine, pyrazinamide, and ethambutol (RIPE therapy), plus levofloxacin for empirical treatment against TB while the other diagnostic tests were pending. A 14-day prednisone course and additional 20-day taper was added to prevent TB-related complications.^16,17  The T-SPOT.TB was positive, the QFT was negative, and the TST had no induration after 48 hours. Interestingly, M.TB PCR was negative in the sputum sample, prompting the addition of azithromycin to provide empirical coverage of NTM organisms. Testing for endemic mycoses revealed a negative Aspergillus Ab and Coccidioides Ab by complement fixation and negative Blastomyces Ab by enzyme immunoassay. Urine Histoplasma antigen testing by enzyme immunoassay was above the level of detection, but below the level of quantification and blood Histoplasma Ab was negative by complement fixation. A skeletal survey, positron emission tomography scan, and MRI were done to further characterize the lucent lesions in the proximal humerus and to investigate any other lesions not previously seen. These revealed lucent lesions in nearly all long bones, some wrist bones, and diffuse bone marrow involvement, which radiology interpreted as consistent with “Jungling disease,” a rare presentation of TB consisting of multifocal lytic bone lesions.¹⁸  A biopsy of 1 lesion revealed nonspecific inflammatory changes, no AFB, and no evidence of malignancy. A chest x-ray for the patient’s mother was also recommended and was negative.

Dr Cameron, Can You Explain the Discordant TB Results?

Her birth in southern Mexico, severe malnutrition, cavitary lesion on CXR, positive T-SPOT.TB, and positive AFB smear pointed toward disseminated TB. We were uncertain why her TB testing results were discordant. The TST responds to hundreds of TB antigens, which can cross-react with the bacillus Calmette-Guérin vaccine and exposure or infection with NTM. IGRAs test for lymphocyte responses to only 3 TB antigens, so are more specific in these patients but can be positive with NTM species including M flavenscens, M kansasii, M marinum, and M szulgai.^9–11,19 

The Centers for Disease Control and Prevention supports that any of the tests can be used as screening tests for TB infection, and many studies reveal that IGRAs are more specific in bacillus Calmette-Guérin-immunized patients.^9–11  Her severe malnutrition may have placed her at risk for having a false negative QFT and TST. Although there is growing literature that T-SPOT.TB may have enhanced performance in immunocompromised hosts,^12,13  no TB tests perform well in these patients. Though a negative M.TB PCR cannot exclude TB disease, the fact that M.TB was not detected in the context of AFB smear-positivity raised our suspicion for NTM organisms.

On hospital day 7, the sputum culture grew Mycobacterium spp, later identified as M. kansasii susceptible to clarithromycin and rifampin. This organism rarely presents with severe disease, so Pediatric Allergy and Immunology was consulted for concern of primary immunodeficiency.²⁰  Evaluation for a primary immunodeficiency included T, B, and natural killer (NK) cell panels, lymphocyte proliferation assay, immunoglobulin levels, ferritin, triglycerides, and fibrinogen levels to screen for immune dysfunction and hemophagocytic lymphohistiocytosis (Table 3, A–C). Whole-exome sequencing and chromosomal microarray were sent as these would not be affected by her nutritional status.

Dr Rider: Can You Explain the Results of Our Patient’s Immune Workup? How Does Malnourishment Affect the Immune System?

Our patient had obvious immune dysfunction, and we needed to determine whether this was a primary or acquired immune deficiency. Possible etiologies of immune dysfunction that could predispose to severe M. kansasii infection are protein-calorie malnutrition, HIV, STAT 1 deficiency, GATA2 deficiency, and any condition previously reported within the Mendelian Susceptibility to Mycobacterial Disease spectrum that may present in the young adult years²¹ ; however, there was no history of recurrent infections, HIV testing on arrival was nonreactive, and per review of her medical record, she had previously normal absolute monocyte and lymphocyte counts documented in 2018. Immunoglobulin levels were within normal ranges. Though she was lymphopenic, the distribution and function of T and B cells were normal. She did have significantly decreased NK cells, but evaluation of her NK cell function and whole-exome sequencing revealed no abnormalities, making a primary immunodeficiency very unlikely. In addition, NK cells are notoriously sensitive to steroids, malnutrition, and other stressors, further reducing the likelihood of a primary NK cell defect.²² 

Malnutrition impairs host-defense and is a known cause of lymphopenia. In cases of severe protein-calorie malnutrition, atrophy of primary lymphoid organs such as premature thymic involution and bone marrow suppression causes leukopenia, increased circulating immature T cells, and decreased CD4/CD8 ratio.^22–24  In fact, severe acute malnutrition is considered the most common cause of immunodeficiency worldwide.^24–26 

The severity of this infection is most likely related to severe malnutrition given her chronic course and low BMI. The point of no return in the immune system is typically when malnutrition leads to profound reductions in the production and function of immune cells,²⁷  decreased hematopoiesis, and reduced migration and extravasation of monocytes, macrophages, dendritic cells, and NK cells.^28,29  Lack of polymorphonuclear cells leads to decreased circulating white blood cells and IL-1b, leading to decreased T-cell activation and signs of systemic inflammation.²⁷ 

On hospital day 25, our patient had received 21 days of RIPE therapy plus levofloxacin and azithromycin. Her 14-day prednisone course was completed, and a 20-day taper had begun. She had also gained 7 pounds. The patient began having chills, night sweats, worsening cough, daily fevers to 103°F, and a systolic ejection murmur. Additional evaluation for infectious diseases was performed for possible nosocomial infections and broader fungal testing. Because Histoplasma is endemic in Guerrero, Mexico and urine Histoplasma Ag testing by enzyme immunoassay was initially detected but not to the level of quantification, she was treated with itraconazole for a short time, but repeat testing was negative. A sputum culture grew Aspergillus fumigatus, and she had worsening consolidations on imaging (Fig 5). A repeat fungal sputum culture and microbial cell free DNA tests were sent, which both identified Mycobacterium kansasii. Gastroenterology was consulted to evaluate for malabsorption. Though malabsorption did not cause her malnutrition, drug levels were low and were adjusted to achieve therapeutic levels (Table 4). The cause of her worsening was presumed to be because of persistent immune reconstitution inflammatory syndrome (IRIS). After 24 days of fevers, her fevers resolved 5 days after restarting prednisone.

Dr Rider: What evidence was there to support a diagnosis of IRIS? Why did IRIS develop if she was already on steroids?

Our patient developed fevers, night sweats, and worsening chest consolidation on imaging. This was concomitant with a 7-pound weight gain, appropriately directed therapy against M. kansasii, and lack of microbiological evidence for additional infections. In this context, evidence for IRIS included prolonged fevers after nutritional rehabilitation and her partial response to steroid therapy.³⁰  Additionally, the development of IRIS among individuals with M.TB has been reported following the initiation of appropriate antitubercular therapy.^31–33 

Regarding the control of IRIS with steroids, we certainly wish to mitigate unnecessary inflammatory disease once IRIS is diagnosed. However, the complete abolition of inflammation would not be possible without globally impairing immunity, which is required to clear NTM disease. Additionally, although expert opinion suggests glucocorticoids to manage IRIS, the precise management of this condition is not well established.^34,35  Given these elements, our patient probably had IRIS and a partial response to glucocorticoid therapy. It should also be mentioned that, although the HIV literature describes IRIS among persons with impaired T-cell mediated immunity, our patient presumably had a completely competent immune system at baseline. Thus, her T-cells should be expected to robustly respond to nutritional repletion and become more difficult to control in the setting of IRIS than in a patient living with HIV who has immune reconstitution via antiretroviral therapy. It is not surprising that IRIS may be more robust and less amenable to complete control when a competent immune response is restored by correcting a secondary impairment like malnutrition.

Dr Cameron, the big question is whether this patient’s malnutrition led to her disseminated M. kansasii or whether a chronic infection led to her malnutrition. What evidence do we have to support either?

NTM do not typically cause severe disease in immunocompetent individuals, thus it would be unexpected to result in such severe malnutrition. Based on her cough beginning 2 weeks before presentation, her negative workup for other conditions leading to increased risk of severe mycobacterial infection, and her subtle restrictive eating behaviors, I think the patient’s severe malnutrition put her at risk for a severe M. kansasii infection.

When is Discharge Safe? What is the Treatment Duration?

In most situations, a patient can be discharged when they are clinically improving, tolerating RIPE therapy, and appropriate follow-up is arranged. The treatment of NTM infections begins with the first negative sputum or respiratory culture and continues for 12 months. Once culture-negative, repeat cultures are not collected unless the patient does not improve as expected.³⁶ 

NTM are ubiquitous in the environment and a known cause of colonization and disease in immunocompromised, and rarely, immunocompetent hosts.^20,21,36,37  NTM pulmonary disease is rare, and the prevalence increases with age.²⁰  In one surveillance study evaluating tuberculosis in children, 104 out of 1732 children were infected with NTM. Of those infected with NTM, 5% were asymptomatic and 5% were hospitalized with NTM pulmonary disease. No children had disseminated disease and most children recovered without treatment.²⁰ 

Our patient had disseminated NTM infection with pulmonary, osseous, and lymph node involvement, which is unexpected in immunocompetent hosts.^21,37,38  NTM infections require intracellular activity in the macrophage in addition to a complex network of T-cells, NK cells, IL-12, IFN-γ, and NF-kb to complete intracellular killing, thus placing those with decreased signaling at risk for severe infections.²¹  Primary immunodeficiency was excluded in our patient, but she had evidence of NK cell dysfunction thought to be caused by her severe malnutrition. She was likely previously colonized with M. kansasii, then major depressive disorder with behavioral calorie restriction, severe protein-calorie malnutrition, and the associated immune dysfunction likely allowed her disease to rapidly progress.

Another unique aspect of our case is the immune reconstitution following the initiation of antimycobacterial treatment and nutritional rehabilitation. IRIS is a known phenomenon in patients living with HIV after the initiation of antiretroviral therapy and patients with M.TB. There have been cases of IRIS in patients coinfected with HIV and M. kansasii.³⁹  There are also a few reports detailing cases of worsening type IRIS following cessation of immunosuppressive drugs,^20,39–41  but none involving patients with severe malnutrition-induced immune deficiency. In our patient’s case, though we were unable to repeat T, B, and NK cell panels to prove recovery of her NK cells, her immune system function presumably improved with nutritional rehabilitation. The diagnosis of IRIS was further supported by her clinical improvement shortly after reinstating immune suppression. This case enhances the understanding of the clinical significance of immune dysfunction in severe malnutrition and demonstrates the risk of immune reconstitution after nutritional rehabilitation in patients with existing infections.

Our patient was discharged to complete a 12-month course of rifampin, ethambutol, azithromycin, moxifloxacin, and slow prednisone taper over 10 weeks. After many follow-up visits with infectious disease, her general practitioner, and subspecialty referrals to gastroenterology, psychiatry, and social work, she continued to struggle with undulating weight and disordered eating. She achieved resolution of cough after 6 months of treatment but was lost to follow-up before the completion of her antimicrobial therapy.

AFB

acid-fast bacilli

CT

computed tomography

CXR

chest x-ray

ED

emergency department

ID

infectious diseases

IGRA

interferon-γ release assay

IRIS

immune reconstitution inflammatory syndrome

NK

natural killer

NTM

nontuberculous mycobacterium

PCR

polymerase chain reaction

QFT

Quantiferon Gold-in-Tube

RIPE

rifampin, isoniazid, pyrazinamide, ethambutol

TB

Mycobacterium tuberculosis

TST

tuberculin skin test